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Michelle Monje
Professor of Neurology and, by courtesy, of Neurosurgery, of Pediatrics, of Pathology and of Psychiatry and Behavioral Sciences
Neurology & Neurological Sciences
Practices at Stanford Medicine Children's Health
Neuro Oncology
Professor, Neurology & Neurological Sciences
Professor (By courtesy), Neurosurgery
Professor (By courtesy), Pediatrics
Professor (By courtesy), Pathology
Professor (By courtesy), Psychiatry and Behavioral Sciences
Member, Bio-X
Member, Institute for Stem Cell Biology and Regenerative Medicine
Member, Maternal & Child Health Research Institute (MCHRI)
Member, Stanford Cancer Institute
Member, Wu Tsai Neurosciences Institute
Investigator, Howard Hughes Medical Institute (2021-)
MacArthur Fellowship, MacArthur Foundation (2021)
Member, National Academy of Medicine (2021)
Presidential Early Career Award for Science and Engineering (PECASE), NIH, White House (2019)
NIH Director's Pioneer Award, NIH (2018-2023)
Neuro-Oncology Investigator Award, American Academy of Neurology (2017)
New Faculty Physician Scientist Translational Research Award, California Institute of Regenerative Medicine (CIRM) (2013 - 2018)
'A' Award, Alex's Lemonade Stand Foundation (2012-2015)
Basic Science IV Award, California Institute of Regenerative Medicine (CIRM) (2012 - 2015)
Peter A. Steck Memorial Award, Pediatric Brain Tumor Foundation (2011)
K08 Mentored Clinical Scientist Career Development Award, National Institutes of Neurological Disorders and Stroke (2010 - 2015)
Young Investigator Award, Hagerty Foundation for Glioma Research (2006)
Boards, Advisory Committees, Professional Organizations
Institutional PI/co-PI, Pediatric Brain Tumor Consortium (PBTC) (2012 - Present)
Scientific Advisory Board, Alex's Lemonade Stand Foundation (2018 - Present)
Editorial Advisory Board, Cancer Cell (2020 - Present)
Editorial Advisory Board, Neuron (2020 - Present)
Fellowship: Stanford Hospital and Clinics Neuro-Oncology Fellowship (2010) CA
Internship: Stanford University Internal Medicine Residency (2005) CA
Medical Education: Stanford University School of Medicine (2004) CA
Board Certification: American Board of Psychiatry and Neurology, Neurology (2008)
Board Certification: United Council for Neurologic Subspecialties, Neuro-Oncology (2013)
Residency: Massachusetts General Hospital (2008) MA
Residency: Brigham and Women's Hospital Harvard Medical School (2008) MA
Subspecialty Board Certification, United Council for Neurological Subspecialties, Neuro-Oncology (2013)
PhD, Stanford University, Neuroscience (2004)
MD, Stanford University (2004)
mmonje@stanford.edu
University - Faculty Department:&nbspNeurology Position: Professor
265 Campus Drive, G3077
Stanford, California 94305-5461
University - Staff Department:&nbspNeurology Position: Faculty On Other Payrolls
Administrative Assistant Julie Hitchcock Administrative Assistant julieh1@stanford.edu
Clinical Division of Child Neurology 265 Campus Dr Rm G3077 Lokey Stem Cell Bldg Palo Alto, CA 94305
Clinical Child Neurology 750 Welch Rd Ste 317 MC 5784 Palo Alto, CA 94304
Clinical Pediatric Oncology Clinic 725 Welch Rd Ste 150 Palo Alto, CA 94304
Monje Lab
Current Research and Scholarly Interests
Much of brain development occurs after birth. Maturation of complex neural circuitry necessary for high-level cognitive and motor functions occurs throughout childhood and young adulthood. Central to the process of developing or strengthening a functional neural circuit is the generation of new glial cells for neuronal support, synapse formation and myelination. In some brain regions, such as the hippocampus, new neuron production occurs throughout postnatal life and is believed to subserve normal memory function.
The Monje Lab studies the molecular and cellular mechanisms of postnatal neurodevelopment. This includes microenvironmental influences on neural precursor cell fate choice in normal neurodevelopment and in disease states. Areas of emphasis include neuronal instruction of gliogenesis, cellular contributions to the neurogenic and gliogenic signaling microenvironment, molecular determinants of neural precursor cell fate, and the role of neural precursor cells in oncogenesis and repair mechanisms. As a practicing neurologist and Neuro-oncologist, Dr Monje is particularly interested in the roles for neural precursor cell function and dysfunction in the origins of pediatric brain tumors and the consequences of cancer treatment. As a paradigm of pediatric gliogenesis, we have been focusing on brainstem tumors, whose spatial and temporal specificity bespeak an underlying developmental cause.
GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG) Recruiting
The primary purpose of this study is to test whether GD2-CAR T cells can be successfully made from immune cells collected from children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) or spinal H3K27M-mutant diffuse midline glioma (DMG). H3K27Mmutant testing will occur as part of standard of care prior to enrollment.
INCB7839 in Treating Children With Recurrent/Progressive High-Grade Gliomas Recruiting
This is a multicenter phase 1 trial of INCB7839 for children with recurrent or progressive high-grade gliomas, including, but not limited to, diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs), after upfront therapy.
Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma Recruiting
This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body's immune system, and may interfere with the ability of tumor cells to grow and spread.
A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma Not Recruiting
Historically, medulloblastoma treatment has been determined by the amount of leftover disease present after surgery, also known as clinical risk (standard vs. high risk). Recent studies have shown that medulloblastoma is made up of distinct molecular subgroups which respond differently to treatment. This suggests that clinical risk alone is not adequate to identify actual risk of recurrence. In order to address this, we will stratify medulloblastoma treatment in this phase II clinical trial based on both clinical risk (low, standard, intermediate, or high risk) and molecular subtype (WNT, SHH, or Non-WNT Non-SHH). This stratified clinical and molecular treatment approach will be used to evaluate the following: - To find out if participants with low-risk WNT tumors can be treated with a lower dose of radiation to the brain and spine, and a lower dose of the chemotherapy drug cyclophosphamide while still achieving the same survival rate as past St. Jude studies with fewer side effects. - To find out if adding targeted chemotherapy after standard chemotherapy will benefit participants with SHH positive tumors. - To find out if adding new chemotherapy agents to the standard chemotherapy will improve the outcome for intermediate and high risk Non-WNT Non-SHH tumors. - To define the cure rate for standard risk Non-WNT Non-SHH tumors treated with reduced dose cyclophosphamide and compare this to participants from the past St. Jude study. All participants on this study will have surgery to remove as much of the primary tumor as safely possible, radiation therapy, and chemotherapy. The amount of radiation therapy and type of chemotherapy received will be determined by the participant's treatment stratum. Treatment stratum assignment will be based on the tumor's molecular subgroup assignment and clinical risk. The participant will be assigned to one of three medulloblastoma subgroups determined by analysis of the tumor tissue for tumor biomarkers: - WNT (Strata W): positive for WNT biomarkers - SHH (Strata S): positive for SHH biomarkers - Non-WNT Non-SHH, Failed, or Indeterminate (Strata N): negative for WNT and SHH biomarkers or results are indeterminable Participants will then be assigned to a clinical risk group (low, standard, intermediate, or high) based on assessment of: - How much tumor is left after surgery - If the cancer has spread to other sites outside the brain [i.e., to the spinal cord or within the fluid surrounding the spinal cord, called cerebrospinal fluid (CSF)] - The appearance of the tumor cells under the microscope - Whether or not there are chromosomal abnormalities in the tumor, and if present, what type (also called cytogenetics analysis)
Stanford is currently not accepting patients for this trial. For more information, please contact Peds Hem/Onc CRAs, 650-723-5535.
Bevacizumab and Lapatinib in Children With Recurrent or Refractory Ependymoma Not Recruiting
The goal of this clinical research study is to learn if the combination of Avastin (bevacizumab) and Tykerb (lapatinib) can help to control ependymoma in pediatric patients. The safety of this drug combination will also be studied.
Stanford is currently not accepting patients for this trial. For more information, please contact Carissa Bailey, (650) 725 - 4708.
Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System Germ Cell Tumors Not Recruiting
This phase II trial studies how well chemotherapy followed by radiation therapy work in treating younger patients with newly diagnosed central nervous system germ cell tumors that have not spread to other parts of the brain, spinal canal, or body (localized). Drugs used as chemotherapy, such as carboplatin, etoposide, and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x rays to kill tumor cells. Giving chemotherapy followed by radiation therapy may kill more tumor cells.
FLT-PET Imaging of Brain Tumors in Children Not Recruiting
Brain tumors are the leading cause of death from solid tumors in children. Tumor imaging is important in the management of these tumors, but current imaging methods have limitations in providing the necessary information for optimal treatment of these patients. The goal of this study is to evaluate the potential utility of positron emission tomography (PET) with 3'-deoxy-3'-[F-18] fluorothymidine (18F-FLT) in the medical management of brain tumors in children. Funding source - FDA Office of Orphan Product Development (OOPD)
Long-term Cognitive, Neuropsychiatric and Functional Outcomes in Adults Who Have Received Chimeric Antigen-Receptor T-Cell (CAR-T) Therapy for Aggressive Lymphoma at Stanford Not Recruiting
This study aims to assess the feasibility of performing neuropsychological testing to measure the cognitive performance of individuals following Axicabtagene ciloleucel CAR-T therapy at Stanford.
Stanford is currently not accepting patients for this trial. For more information, please contact Brian J Scott, MD, bjscott@stanford.edu.
Methylphenidate HCl or Modafinil in Treating Young Patients With Excessive Daytime Sleepiness After Cancer Therapy Not Recruiting
RATIONALE: Methylphenidate hydrochloride or modafinil may help reduce daytime sleepiness and improve the quality of life of patients with excessive daytime sleepiness after cancer therapy. It is not yet known whether methylphenidate hydrochloride or modafinil are more effective than a placebo in reducing daytime sleepiness in these patients. PURPOSE: This randomized phase II trial is studying methylphenidate hydrochloride or modafinil to see how well they work compared with a placebo in treating young patients with excessive daytime sleepiness after cancer therapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Lew, (650) 725 - 4318.
Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors Not Recruiting
This phase I trial studies the side effects and best dose of palbociclib isethionate in treating younger patients with central nervous system tumors that have grown, come back, or not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Prianka Kumar, 650-724-3866.
Peginterferon Alfa-2b in Younger Patients With Craniopharyngioma That is Recurrent or Cannot Be Removed By Surgery Not Recruiting
This phase II trial studies how well peginterferon alfa-2b works in treating younger patients with craniopharyngioma that is recurrent or cannot be removed by surgery. Peginterferon alfa-2b may interfere with the growth of tumor cells and slow the growth of craniopharyngioma.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
Phase I Rindopepimut After Conventional Radiation in Children w/ Diffuse Intrinsic Pontine Gliomas Not Recruiting
This is a research study of patients with diffuse intrinsic pontine gliomas. We hope to learn about the safety and efficacy of treating pediatric diffuse intrinsic pontine glioma patients with the EGFRvIII peptide vaccine after conventional radiation.
Stanford is currently not accepting patients for this trial. For more information, please contact Christina Huang, 650-723-0574.
Phase I Study of APX005M in Pediatric CNS Tumors Not Recruiting
This phase I trial studies the side effects and best dose of APX005M in treating younger patients with primary malignant central nervous system tumor that is growing, spreading, or getting worse (progressive), or newly diagnosed diffuse intrinsic pontine glioma. APX005M can trigger activation of B cells, monocytes, and dendritic cells and stimulat cytokine release from lymphocytes and monocytes. APX005M can mediate a direct cytotoxic effect on CD40+ tumor cells.
Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Monje, 650-721-5750.
Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma Not Recruiting
This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Testing the Safety and Tolerability of CX-4945 in Patients With Recurrent Medulloblastoma Who May or May Not Have Surgery Not Recruiting
This is a multi center, Phase I, Phase II and surgical study of the CX-4945 drug (silmitasertib sodium) for patients with recurrent SHH (Sonic Hedgehog) medulloblastoma
Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma Not Recruiting
This phase I trial studies the side effects and best dose of panobinostat in treating younger patients with diffuse intrinsic pontine glioma (DIPG). Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stratum 1 treats patients with DIPG that has returned or gotten worse (progressed). Stratum 2 treats patients with DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) that has not yet gotten worse. Currently, only Stratum 2 is enrolling patients.
Vismodegib in Treating Younger Patients With Recurrent or Refractory Medulloblastoma Not Recruiting
This phase II trial studies how well vismodegib works in treating younger patients with recurrent or refractory medulloblastoma. Vismodegib may slow the growth of tumor cells.
Independent Studies (19)
Directed Investigation
BIOE 392 (Win, Spr)
Directed Reading in Cancer Biology
CBIO 299 (Win, Spr)
Directed Reading in Neurology and Neurological Science
NENS 299 (Aut, Win, Spr)
Directed Reading in Neurosciences
NEPR 299 (Aut, Win, Spr)
Directed Reading in Stem Cell Biology and Regenerative Medicine
STEMREM 299 (Win, Spr)
Early Clinical Experience in Neurology and Neurological Sciences
CBIO 399 (Aut, Win, Spr, Sum)
NEPR 399 (Aut, Win, Spr, Sum)
STEMREM 399 (Aut, Win, Spr, Sum)
HUMBIO 194 (Aut, Win, Spr)
Medical Scholars Research
NENS 370 (Aut, Win, Spr, Sum)
Out-of-Department Advanced Research Laboratory in Bioengineering
BIOE 191X (Aut, Win, Spr, Sum)
Out-of-Department Undergraduate Research
BIO 199X (Aut, Win, Spr)
Research in Human Biology
Teaching in Cancer Biology
CBIO 260 (Spr)
Stanford Advisees
Med Scholar Project Advisor
Sol Savchuk
Doctoral Dissertation Reader (AC)
Caroline Arellano-Garcia, Gustavo Chau Loo Kung, Carolyn Dundes, Manasi Iyer, Benjamin Oberlton, Anay Ram Reddy, David Wang
Postdoctoral Faculty Sponsor
Tara Barron, Shawn Gillespie, Albina Ibrayeva, Yoon Seok Kim, Minhui Su, Haojun Xu, Belgin Yalcin, Daniel Zamler
Doctoral Dissertation Advisor (AC)
Lehi Acosta-Alvarez, Karen Malacon, Rebecca Mancusi, Kiarash Shamardani
Graduate and Fellowship Programs
Cancer Biology (Phd Program)
Developmental Biology (Phd Program)
Neurosciences (Phd Program)
Stem Cell Biology and Regenerative Medicine (Phd Program)
Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M. H., Wood, J., O'Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., Mancusi, R., Yalçın, B., Taylor, K. R., Acosta-Alvarez, L., Malacon, K., Keough, M. B., Ni, L., Woo, P. J., Contreras-Esquivel, D., Toland, A. M., Gehlhausen, J. R., Klein, J., Takahashi, T., Silva, J., Israelow, B., Lucas, C., Mao, T., Peña-Hernández, M. A., Tabachnikova, A., Homer, R. J., Tabacof, L., Tosto-Mancuso, J., Breyman, E., Kontorovich, A., McCarthy, D., Quezado, M., Vogel, H., Hefti, M. M., Perl, D. P., Liddelow, S., Folkerth, R., Putrino, D., Nath, A., Iwasaki, A., Monje, M. 2022
COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
View details for DOI 10.1016/j.cell.2022.06.008
GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature Majzner, R. G., Ramakrishna, S., Yeom, K. W., Patel, S., Chinnasamy, H., Schultz, L. M., Richards, R. M., Jiang, L., Barsan, V., Mancusi, R., Geraghty, A. C., Good, Z., Mochizuki, A. Y., Gillespie, S. M., Toland, A. M., Mahdi, J., Reschke, A., Nie, E., Chau, I. J., Rotiroti, M. C., Mount, C. W., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Erickson, C., Green, S., Kunicki, M., Fujimoto, M., Ehlinger, Z., Reynolds, W., Kurra, S., Warren, K. E., Prabhu, S., Vogel, H., Rasmussen, L., Cornell, T. T., Partap, S., Fisher, P. G., Campen, C. J., Filbin, M. G., Grant, G., Sahaf, B., Davis, K. L., Feldman, S. A., Mackall, C. L., Monje, M. 2022
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMG) are universally lethal paediatric central nervous system tumours1. We previously discovered that the disialoganglioside GD2 is highly expressed on H3K27M-mutant glioma cells and demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutant DIPG/DMG treated with GD2-CAR T cells (GD2-CART) at dose level 1 (1e6 GD2-CAR T cells/kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T infusions administered intracerebroventricularly3. Toxicity was largely related to tumor location and reversible with intensive supportive care. On-target, off-tumor toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Proinflammatory cytokines were increased in plasma and cerebrospinal fluid (CSF). Transcriptomic analyses of 65,598 single cells from CAR T cell products and CSF elucidate heterogeneity in response between subjects and administration routes. These early results underscore the promise of this approach for H3K27M+ DIPG/DMG therapy.
NF1 mutation drives neuronalactivity-dependent initiation of optic glioma. Nature Pan, Y., Hysinger, J. D., Barron, T., Schindler, N. F., Cobb, O., Guo, X., Yalcin, B., Anastasaki, C., Mulinyawe, S. B., Ponnuswami, A., Scheaffer, S., Ma, Y., Chang, K., Xia, X., Toonen, J. A., Lennon, J. J., Gibson, E. M., Huguenard, J. R., Liau, L. M., Goldberg, J. L., Monje, M., Gutmann, D. H. 2021
Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with theneurofibromatosis1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.
Roadmap for the Emerging Field of Cancer Neuroscience. Cell Monje, M., Borniger, J. C., D'Silva, N. J., Deneen, B., Dirks, P. B., Fattahi, F., Frenette, P. S., Garzia, L., Gutmann, D. H., Hanahan, D., Hervey-Jumper, S. L., Hondermarck, H., Hurov, J. B., Kepecs, A., Knox, S. M., Lloyd, A. C., Magnon, C., Saloman, J. L., Segal, R. A., Sloan, E. K., Sun, X., Taylor, M. D., Tracey, K. J., Trotman, L. C., Tuveson, D. A., Wang, T. C., White, R. A., Winkler, F. 2020; 181 (2): 219–22
Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of "cancer neuroscience" and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.
Electrical and synaptic integration of glioma into neural circuits. Nature Venkatesh, H. S., Morishita, W., Geraghty, A. C., Silverbush, D., Gillespie, S. M., Arzt, M., Tam, L. T., Espenel, C., Ponnuswami, A., Ni, L., Woo, P. J., Taylor, K. R., Agarwal, A., Regev, A., Brang, D., Vogel, H., Hervey-Jumper, S., Bergles, D. E., Suva, M. L., Malenka, R. C., Monje, M. 2019
High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.
View details for DOI 10.1038/s41586-019-1563-y
Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment CELL Gibson, E. M., Nagaraja, S., Ocampo, A., Tam, L. T., Wood, L. S., Pallegar, P. N., Greene, J. J., Geraghty, A. C., Goldstein, A. K., Ni, L., Woo, P. J., Barres, B. A., Liddelow, S., Vogel, H., Monje, M. 2019; 176 (1-2): 43-+
Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment. Neuron Geraghty, A. C., Gibson, E. M., Ghanem, R. A., Greene, J. J., Ocampo, A. n., Goldstein, A. K., Ni, L. n., Yang, T. n., Marton, R. M., Paşca, S. P., Greenberg, M. E., Longo, F. M., Monje, M. n. 2019
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
View details for DOI 10.1016/j.neuron.2019.04.032
Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas NATURE MEDICINE Mount, C. W., Majzner, R. G., Sundaresh, S., Arnold, E. P., Kadapakkam, M., Haile, S., Labanieh, L., Hulleman, E., Woo, P. J., Rietberg, S. P., Vogel, H., Monje, M., Mackall, C. L. 2018; 24 (5): 572-+
View details for DOI 10.1038/s41591-018-0006-x
Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma. Cell Qin, E. Y., Cooper, D. D., Abbott, K. L., Lennon, J. n., Nagaraja, S. n., Mackay, A. n., Jones, C. n., Vogel, H. n., Jackson, P. K., Monje, M. n. 2017; 170 (5): 845–59.e19
The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion. PAPERCLIP.
Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature Venkatesh, H. S., Tam, L. T., Woo, P. J., Lennon, J. n., Nagaraja, S. n., Gillespie, S. M., Ni, J. n., Duveau, D. Y., Morris, P. J., Zhao, J. J., Thomas, C. J., Monje, M. n. 2017; 549 (7673): 533–37
High-grade gliomas (HGG) are a devastating group of cancers, and represent the leading cause of brain tumour-related death in both children and adults. Therapies aimed at mechanisms intrinsic to glioma cells have translated to only limited success; effective therapeutic strategies will need also to target elements of the tumour microenvironment that promote glioma progression. Neuronal activity promotes the growth of a range of molecularly and clinically distinct HGG types, including adult and paediatric glioblastoma (GBM), anaplastic oligodendroglioma, and diffuse intrinsic pontine glioma (DIPG). An important mechanism that mediates this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic adhesion molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway. However, the necessity of NLGN3 for glioma growth, the proteolytic mechanism of NLGN3 secretion, and the further molecular consequences of NLGN3 secretion in glioma cells remain unknown. Here we show that HGG growth depends on microenvironmental NLGN3, identify signalling cascades downstream of NLGN3 binding in glioma, and determine a therapeutically targetable mechanism of secretion. Patient-derived orthotopic xenografts of paediatric GBM, DIPG and adult GBM fail to grow in Nlgn3 knockout mice. NLGN3 stimulates several oncogenic pathways, such as early focal adhesion kinase activation upstream of PI3K-mTOR, and induces transcriptional changes that include upregulation of several synapse-related genes in glioma cells. NLGN3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. ADAM10 inhibitors prevent the release of NLGN3 into the tumour microenvironment and robustly block HGG xenograft growth. This work defines a promising strategy for targeting NLGN3 secretion, which could prove transformative for HGG therapy.
Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion CELL Venkatesh, H. S., Johung, T. B., Caretti, V., Noll, A., Tang, Y., Nagaraja, S., Gibson, E. M., Mount, C. W., Polepalli, J., Mitra, S. S., Woo, P. J., Malenka, R. C., Vogel, H., Bredel, M., Mallick, P., Monje, M. 2015; 161 (4): 803-816
Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.
Neuronal Activity Promotes Oligodendrogenesis and Adaptive Myelination in the Mammalian Brain SCIENCE Gibson, E. M., Purger, D., Mount, C. W., Goldstein, A. K., Lin, G. L., Wood, L. S., Inema, I., Miller, S. E., Bieri, G., Zuchero, J. B., Barres, B. A., Woo, P. J., Vogel, H., Monje, M. 2014; 344 (6183): 487-?
Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.
View details for DOI 10.1126/science.1252304
View details for PubMedCentralID PMC4096908
Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1. Nature communications Anastasaki, C., Mo, J., Chen, J., Chatterjee, J., Pan, Y., Scheaffer, S. M., Cobb, O., Monje, M., Le, L. Q., Gutmann, D. H. 2022; 13 (1): 2785
Neuronal activity is emerging as a driver of central and peripheral nervous system cancers. Here, we examined neuronal physiology in mouse models of the tumor predisposition syndrome Neurofibromatosis-1 (NF1), with different propensities to develop nervous system cancers. We show that central and peripheral nervous system neurons from mice with tumor-causing Nf1 gene mutations exhibit hyperexcitability and increased secretion of activity-dependent tumor-promoting paracrine factors. We discovered a neurofibroma mitogen (COL1A2) produced by peripheral neurons in an activity-regulated manner, which increases NF1-deficient Schwann cell proliferation, establishing that neurofibromas are regulated by neuronal activity. In contrast, mice with the Arg1809Cys Nf1 mutation, found in NF1 patients lacking neurofibromas or optic gliomas, do not exhibit neuronal hyperexcitability or develop these NF1-associated tumors. The hyperexcitability of tumor-prone Nf1-mutant neurons results from reduced NF1-regulated hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function, such that neuronal excitability, activity-regulated paracrine factor production, and tumor progression are attenuated by HCN channel activation. Collectively, these findings reveal that NF1 mutations act at the level of neurons to modify tumor predisposition by increasing neuronal excitability and activity-regulated paracrine factor production.
H3-K27M-mutant nucleosomes interact with MLL1 to shape the glioma epigenetic landscape. Cell reports Furth, N., Algranati, D., Dassa, B., Beresh, O., Fedyuk, V., Morris, N., Kasper, L. H., Jones, D., Monje, M., Baker, S. J., Shema, E. 2022; 39 (7): 110836
Cancer-associated mutations in genes encoding histones dramatically reshape chromatin and support tumorigenesis. Lysine to methionine substitution of residue 27 on histone H3 (K27M) is a driver mutation in high-grade pediatric gliomas, known to abrogate polycomb repressive complex 2 (PRC2) activity. We applied single-molecule systems to image individual nucleosomes and delineate the combinatorial epigenetic patterns associated with H3-K27M expression. We found that chromatin marks on H3-K27M-mutant nucleosomes are dictated both by their incorporation preferences and by intrinsic properties of the mutation. Mutant nucleosomes not only preferentially bind PRC2 but also directly interact with MLL1, leading to genome-wide redistribution of H3K4me3. H3-K27M-mediated deregulation of repressive and active chromatin marks leads to unbalanced "bivalent" chromatin, which may support a poorly differentiated cellular state. This study provides evidence for a direct effect of H3-K27M oncohistone on the MLL1-H3K4me3 pathway and highlights the capability of single-molecule tools to reveal mechanisms of chromatin deregulation in cancer.
View details for DOI 10.1016/j.celrep.2022.110836
Characteristics of Children ≤36 Months of Age with Diffuse Intrinsic Pontine Glioma (DIPG): A Report from the International DIPG Registry. Neuro-oncology Bartlett, A., Lane, A., Chaney, B., Escorza, N. Y., Black, K., Cochrane, A., Minturn, J., Bartels, U., Warren, K., Hansford, J., Ziegler, D., Diez, B., Goldman, S., Packer, R., Kieran, M., DeWire-Schottmiller, M., Erker, C., Monje-Deisseroth, M., Wagner, L., Koschmann, C., Dorris, K., Shih, C., Hassall, T., Samson, Y., Fisher, P., Wang, S. S., Tsui, K., Sevlever, G., Zhu, X., Dexheimer, P., Asher, A., Fuller, C., Drissi, R., Jones, B., Leach, J., Fouladi, M. 2022
BACKGROUND: Children ≤36 months with Diffuse Intrinsic Pontine Glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes.METHODS: Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed.RESULTS: Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥ 5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (p=0.018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation.CONCLUSIONS: Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.
View details for DOI 10.1093/neuonc/noac123
Maladaptive myelination promotes generalized epilepsy progression. Nature neuroscience Knowles, J. K., Xu, H., Soane, C., Batra, A., Saucedo, T., Frost, E., Tam, L. T., Fraga, D., Ni, L., Villar, K., Talmi, S., Huguenard, J. R., Monje, M. 2022
Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.
Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. eLife Reinitz, F., Chen, E. Y., Nicolis di Robilant, B., Chuluun, B., Antony, J., Jones, R. C., Gubbi, N., Lee, K., Ho, W. H., Kolluru, S. S., Qian, D., Adorno, M., Piltti, K., Anderson, A., Monje, M., Heller, H. C., Quake, S. R., Clarke, M. F. 2022; 11
Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the BMP pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.'
View details for DOI 10.7554/eLife.66037
A light-gated transcriptional recorder for detecting cell-cell contacts. eLife Cho, K. F., Gillespie, S. M., Kalogriopoulos, N. A., Quezada, M. A., Jacko, M., Monje, M., Ting, A. Y. 2022; 11
Technologies for detecting cell-cell contacts are powerful tools for studying a wide range of biological processes, from neuronal signaling to cancer-immune interactions within the tumor microenvironment. Here, we report TRACC (Transcriptional Readout Activated by Cell-cell Contacts), a GPCR-based transcriptional recorder of cellular contacts, which converts contact events into stable transgene expression. TRACC is derived from our previous protein-protein interaction recorders, SPARK (Kim et al., 2017) and SPARK2 (Kim et al., 2019), reported in this journal. TRACC incorporates light gating via the light-oxygen-voltage-sensing (LOV) domain, which provides user-defined temporal control of tool activation and reduces background. We show that TRACC detects cell-cell contacts with high specificity and sensitivity in mammalian cell culture and that it can be used to interrogate interactions between neurons and glioma, a form of brain cancer.
Neural Signaling in Cancer. Annual review of neuroscience Keough, M. B., Monje, M. 2022
Nervous system activity regulates development, homeostasis, and plasticity of the brain as well as other organs in the body. These mechanisms are subverted in cancer to propel malignant growth. In turn, cancers modulate neural structure and function to augment growth-promoting neural signaling in the tumor microenvironment. Approaching cancer biology from a neuroscience perspective will elucidate new therapeutic strategies for presently lethal forms of cancer. In this review, we highlight the neural signaling mechanisms recapitulated in primary brain tumors, brain metastases, and solid tumors throughout the body that regulate cancer progression. Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
View details for DOI 10.1146/annurev-neuro-111020-092702
Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication. Nature medicine Theruvath, J., Menard, M., Smith, B. A., Linde, M. H., Coles, G. L., Dalton, G. N., Wu, W., Kiru, L., Delaidelli, A., Sotillo, E., Silberstein, J. L., Geraghty, A. C., Banuelos, A., Radosevich, M. T., Dhingra, S., Heitzeneder, S., Tousley, A., Lattin, J., Xu, P., Huang, J., Nasholm, N., He, A., Kuo, T. C., Sangalang, E. R., Pons, J., Barkal, A., Brewer, R. E., Marjon, K. D., Vilches-Moure, J. G., Marshall, P. L., Fernandes, R., Monje, M., Cochran, J. R., Sorensen, P. H., Daldrup-Link, H. E., Weissman, I. L., Sage, J., Majeti, R., Bertozzi, C. R., Weiss, W. A., Mackall, C. L., Majzner, R. G. 1800
The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.
View details for DOI 10.1038/s41591-021-01625-x
Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry. Neuro-oncology Erker, C., Lane, A., Chaney, B., Leary, S., Minturn, J. E., Bartels, U., Packer, R. J., Dorris, K., Gottardo, N. G., Warren, K. E., Broniscer, A., Kieran, M. W., Zhu, X., White, P., Dexheimer, P. J., Black, K., Asher, A., DeWire, M., Hansford, J. R., Gururangan, S., Nazarian, J., Ziegler, D. S., Sandler, E., Bartlett, A., Goldman, S., Shih, C., Hassall, T., Dholaria, H., Bandopadhayay, P., Samson, Y., Monje, M., Fisher, P. G., Dodgshun, A., Parkin, S., Chintagumpala, M., Tsui, K., Gass, D., Larouche, V., Broxson, E., Garcia Lombardi, M., Wang, S. S., Ma, J., Hawkins, C., Hamideh, D., Wagner, L., Koschmann, C., Fuller, C., Drissi, R., Jones, B. V., Leach, J., Fouladi, M. 1800; 24 (1): 141-152
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR).METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months).RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival.CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
View details for DOI 10.1093/neuonc/noab140
Accuracy of Central Neuro-Imaging Review of DIPG Compared with Histopathology in the International DIPG Registry. Neuro-oncology Lazow, M. A., Fuller, C., DeWire, M., Lane, A., Bandopadhayay, P., Bartels, U., Bouffet, E., Cheng, S., Cohen, K. J., Cooney, T. M., Coven, S. L., Dholaria, H., Diez, B., Dorris, K., El-Ayadi, M., El-Sheikh, A., Fisher, P. G., Fonseca, A., Lombardi, M. G., Greiner, R. J., Goldman, S., Gottardo, N., Gururangan, S., Hansford, J. R., Hassall, T., Hawkins, C., Kilburn, L., Koschmann, C., Leary, S. E., Ma, J., Minturn, J. E., Monje-Deisseroth, M., Packer, R., Samson, Y., Sandler, E. S., Sevlever, G., Tinkle, C. L., Tsui, K., Wagner, L. M., Zaghloul, M., Ziegler, D. S., Chaney, B., Black, K., Asher, A., Drissi, R., Fouladi, M., Jones, B. V., Leach, J. L. 2021
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential.METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included non-pontine origin, <50% pontine involvement, focally exophytic morphology, sharply-defined margins, and/or marked diffusion restriction throughout.RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly non-diffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to non-pontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p<0.001), and central neuro-imaging impression was prognostic of overall survival.CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.
Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma. Nature communications He, C., Xu, K., Zhu, X., Dunphy, P. S., Gudenas, B., Lin, W., Twarog, N., Hover, L. D., Kwon, C., Kasper, L. H., Zhang, J., Li, X., Dalton, J., Jonchere, B., Mercer, K. S., Currier, D. G., Caufield, W., Wang, Y., Xie, J., Broniscer, A., Wetmore, C., Upadhyaya, S. A., Qaddoumi, I., Klimo, P., Boop, F., Gajjar, A., Zhang, J., Orr, B. A., Robinson, G. W., Monje, M., Freeman Iii, B. B., Roussel, M. F., Northcott, P. A., Chen, T., Rankovic, Z., Wu, G., Chiang, J., Tinkle, C. L., Shelat, A. A., Baker, S. J. 2021; 12 (1): 4089
Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. Here we report establishment of 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulate histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and include rare subgroups not well-represented by existing models. We deploy 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predict variable in vivo response to PI3K/mTOR and MEK pathway inhibitors. These unique new models and an online interactive data portal for exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.
GD2 CAR T cells mediate clinical activity and manageable toxicity in children and young adults with DIPG and H3K27M-mutated diffuse midline gliomas. Majzner, R. G., Ramakrishna, S., Mochizuki, A., Patel, S., Chinnasamy, H., Yeom, K., Schultz, L., Richards, R., Campen, C., Reschke, A., Mahdi, J., Toland, A., Baggott, C., Mavroukakis, S., Egeler, E., Moon, J., Landrum, K., Erickson, C., Rasmussen, L., Barsan, V., Tamaresis, J. S., Marcy, A., Kunicki, M., Fujimoto, M., Ehlinger, Z., Kurra, S., Cornell, T., Partap, S., Fisher, P., Grant, G., Vogel, H., Sahaf, B., Davis, K., Feldman, S., Mackall, C. L., Monje, M. AMER ASSOC CANCER RESEARCH. 2021
Unravelling the Mechanisms of Cancer-Related Cognitive Dysfunction in Non-Central Nervous System Cancer. JAMA oncology Hervey-Jumper, S. L., Monje, M. 2021
View details for DOI 10.1001/jamaoncol.2021.1900
Partitioned glioma heritability shows subtype-specific enrichment in immune cells. Neuro-oncology Ostrom, Q. T., Edelson, J., Byun, J., Han, Y., Kinnersley, B., Melin, B., Houlston, R. S., Monje, M., Walsh, K. M., Amos, C. I., Bondy, M. L. 2021
BACKGROUND: Epidemiological studies of adult glioma have identified genetic syndromes and 25 heritable risk loci that modify individual risk for glioma, as well increased risk in association with exposure to ionizing radiation and decreased risk in association with allergies. In this analysis we assess whether there is shared genome-wide genetic architecture between glioma and atopic/autoimmune diseases.METHODS: Using summary statistics from a glioma genome-wide association studies (GWAS) meta-analysis, we identified significant enrichment for risk variants associated with gene expression changes in immune cell populations. We also estimated genetic correlations between glioma and autoimmune, atopic, and hematologic traits using LDscore regression, which leverages genome-wide single nucleotide polymorphism (SNP) associations and patterns of linkage disequilibrium.RESULTS: Nominally significant negative correlations were observed for glioblastoma and primary biliary cirrhosis (rg=-0.26, p=0.0228), and for non-glioblastoma gliomas and celiac disease (rg=-0.32, p=0.0109). Our analyses implicate dendritic cells (GB pHM= 0.0306 and non-GB pHM=0.0186) in mediating both glioblastoma and non-glioblastoma genetic predisposition, with glioblastoma-specific associations identified in natural killer (NK) (pHM=0.0201) and stem cells (pHM=0.0265).CONCLUSIONS: This analysis identifies putative new associations between glioma and autoimmune conditions with genomic architecture that is inversely correlated with that of glioma and that T cells, NK cells, and myeloid cells are involved in mediating glioma predisposition. This provides further evidence that increased activation of the acquired immune system may modify individual susceptibility to glioma.
Microglia in Cancer Therapy-Related Cognitive Impairment. Trends in neurosciences Gibson, E. M., Monje, M. 2021
Millions of cancer survivors experience a persistent neurological syndrome that includes deficits in memory, attention, information processing, and mental health. Cancer therapy-related cognitive impairment can cause mild to severe disruptions to quality of life for these cancer survivors. Understanding the cellular and molecular underpinnings of this disorder will facilitate new therapeutic strategies aimed at ameliorating these long-lasting impairments. Accumulating evidence suggests that a range of cancer therapies induce persistent activation of the brain's resident immune cells, microglia. Cancer therapy-induced microglial activation disrupts numerous mechanisms of neuroplasticity, and emerging findings suggest that this impairment in plasticity is central to cancer therapy-related cognitive impairment. This review explores reactive microglial dysregulation of neural circuit structure and function following cancer therapy.
View details for DOI 10.1016/j.tins.2021.02.003
MRI-based radiomics for prognosis of pediatric diffuse intrinsic pontine glioma: an international study. Neuro-oncology advances Tam, L. T., Yeom, K. W., Wright, J. N., Jaju, A., Radmanesh, A., Han, M., Toescu, S., Maleki, M., Chen, E., Campion, A., Lai, H. A., Eghbal, A. A., Oztekin, O., Mankad, K., Hargrave, D., Jacques, T. S., Goetti, R., Lober, R. M., Cheshier, S. H., Napel, S., Said, M., Aquilina, K., Ho, C. Y., Monje, M., Vitanza, N. A., Mattonen, S. A. 2021; 3 (1): vdab042
Background: Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors. Presently, MRI is the mainstay of disease diagnosis and surveillance. We identify clinically significant computational features from MRI and create a prognostic machine learning model.Methods: We isolated tumor volumes of T1-post-contrast (T1) and T2-weighted (T2) MRIs from 177 treatment-naive DIPG patients from an international cohort for model training and testing. The Quantitative Image Feature Pipeline and PyRadiomics was used for feature extraction. Ten-fold cross-validation of least absolute shrinkage and selection operator Cox regression selected optimal features to predict overall survival in the training dataset and tested in the independent testing dataset. We analyzed model performance using clinical variables (age at diagnosis and sex) only, radiomics only, and radiomics plus clinical variables.Results: All selected features were intensity and texture-based on the wavelet-filtered images (3 T1 gray-level co-occurrence matrix (GLCM) texture features, T2 GLCM texture feature, and T2 first-order mean). This multivariable Cox model demonstrated a concordance of 0.68 (95% CI: 0.61-0.74) in the training dataset, significantly outperforming the clinical-only model (C = 0.57 [95% CI: 0.49-0.64]). Adding clinical features to radiomics slightly improved performance (C = 0.70 [95% CI: 0.64-0.77]). The combined radiomics and clinical model was validated in the independent testing dataset (C = 0.59 [95% CI: 0.51-0.67], Noether's test P = .02).Conclusions: In this international study, we demonstrate the use of radiomic signatures to create a machine learning model for DIPG prognostication. Standardized, quantitative approaches that objectively measure DIPG changes, including computational MRI evaluation, could offer new approaches to assessing tumor phenotype and serve a future role for optimizing clinical trial eligibility and tumor surveillance.
View details for DOI 10.1093/noajnl/vdab042
Microenvironmental interactions of oligodendroglial cells. Developmental cell Yalçın, B., Monje, M. 2021
Developmental myelination is a protracted process that extends well into postnatal life. Cell-intrinsic mechanisms operate in myelin-forming oligodendrocytes, as well as microenvironmental interactions that guide and modulate every aspect of myelination, from oligodendrocyte precursor cell migration to oligodendrocyte differentiation and the formation of stable myelin internodes. During development and throughout adult life, neuron-oligodendroglial interactions shape activity and experience-dependent myelin adaptations to fine-tune neural circuit dynamics and promote healthy neurological function.
View details for DOI 10.1016/j.devcel.2021.06.006
Spinal Cord Injury - Healing from Within. The New England journal of medicine Monje, M. n. 2021; 384 (2): 182–84
View details for DOI 10.1056/NEJMcibr2030836
The bright and the dark side of myelin plasticity: Neuron-glial interactions in health and disease. Seminars in cell & developmental biology Monje, M., Karadottir, R. T. 2020
Neuron-glial interactions shape neural circuit establishment, refinement and function. One of the key neuron-glial interactions takes place between axons and oligodendroglial precursor cells. Interactions between neurons and oligodendrocyte precursor cells (OPCs) promote OPC proliferation, generation of new oligodendrocytes and myelination, shaping myelin development and ongoing adaptive myelin plasticity in the brain. Communication between neurons and OPCs can be broadly divided into paracrine and synaptic mechanisms. Following the Nobel mini-symposium "The Dark Side of the Brain" in late 2019 at the Karolinska Institutet, this mini-review will focus on the bright and dark sides of neuron-glial interactions and discuss paracrine and synaptic interactions between neurons and OPCs and their malignant counterparts.
View details for DOI 10.1016/j.semcdb.2020.11.009
Pharmacologic inhibition of lysine specific demethylase-1 (LSD1) as a therapeutic and immune-sensitization strategy in pediatric high grade glioma (pHGG). Neuro-oncology Bailey, C. P., Figueroa, M., Gangadharan, A., Yang, Y., Romero, M. M., Kennis, B. A., Yadavilli, S., Henry, V., Collier, T., Monje, M., Lee, D. A., Wang, L., Nazarian, J., Gopalakrishnan, V., Zaky, W., Becher, O. J., Chandra, J. 2020
BACKGROUND: Diffuse midline gliomas (DMG), including brainstem DIPG, are incurable pediatric high grade gliomas (pHGG). Mutations in the H3 histone tail (H3.1/3.3-K27M) are a feature of DIPG, rendering them therapeutically sensitive to small-molecule inhibition of chromatin modifiers. Pharmacological inhibition of lysine specific demethylase-1 (LSD1) is clinically relevant but has not been carefully investigated in pHGG or DIPG.METHODS: Patient-derived DIPG cell lines, orthotopic mouse models, and pHGG datasets were used to evaluate effects of LSD1 inhibitors on cytotoxicity and immune gene expression. Immune cell cytotoxicity was assessed in DIPG cells pre-treated with LSD1 inhibitors and informatics platforms were used to determine immune infiltration of pHGG.RESULTS: Selective cytotoxicity and an immunogenic gene signature was established in DIPG cell lines using clinically-relevant LSD1 inhibitors. Pediatric HGG patient sequencing data demonstrated survival benefit of this LSD1-dependent gene signature. Pre-treatment of DIPG with these inhibitors increased lysis by natural killer (NK) cells. Catalytic LSD1 inhibitors induced tumor regression and augmented NK cell infusion in vivo to reduce tumor burden. CIBERSORT analysis of patient data confirmed NK infiltration is beneficial to patient survival while CD8 T-cells are negatively prognostic. Catalytic LSD1 inhibitors are non-perturbing to NK cells while scaffolding LSD1 inhibitors are toxic to NK cells and do not induce the gene signature in DIPG cells.CONCLUSIONS: LSD1 inhibition using catalytic inhibitors is both selectively cytotoxic and promotes an immune gene signature that increases NK cell killing in vitro and in vivo, representing a therapeutic opportunity for pHGG.
View details for DOI 10.1093/neuonc/noaa058
Activity Shapes Neural Circuit Form and Function: A Historical Perspective. The Journal of neuroscience : the official journal of the Society for Neuroscience Pan, Y. n., Monje, M. n. 2020; 40 (5): 944–54
The brilliant and often prescient hypotheses of Ramon y Cajal have proven foundational for modern neuroscience, but his statement that "In adult centers the nerve paths are something fixed, ended, immutable … " is an exception that did not stand the test of empirical study. Mechanisms of cellular and circuit-level plasticity continue to shape and reshape many regions of the adult nervous system long after the neurodevelopmental period. Initially focused on neurons alone, the field has followed a meteoric trajectory in understanding of activity-regulated neurodevelopment and ongoing neuroplasticity with an arc toward appreciating neuron-glial interactions and the role that each neural cell type plays in shaping adaptable neural circuity. In this review, as part of a celebration of the 50th anniversary of Society for Neuroscience, we provide a historical perspective, following this arc of inquiry from neuronal to neuron-glial mechanisms by which activity and experience modulate circuit structure and function. The scope of this consideration is broad, and it will not be possible to cover the wealth of knowledge about all aspects of activity-dependent circuit development and plasticity in depth.
View details for DOI 10.1523/JNEUROSCI.0740-19.2019
The Neural Regulation of Cancer ANNUAL REVIEW OF CANCER BIOLOGY, VOL 4 Gillespie, S., Monje, M., Jacks, T., Sawyers, C. L. 2020; 4: 371–90
View details for DOI 10.1146/annurev-cancerbio-030419-033349
Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Nature medicine Theruvath, J. n., Sotillo, E. n., Mount, C. W., Graef, C. M., Delaidelli, A. n., Heitzeneder, S. n., Labanieh, L. n., Dhingra, S. n., Leruste, A. n., Majzner, R. G., Xu, P. n., Mueller, S. n., Yecies, D. W., Finetti, M. A., Williamson, D. n., Johann, P. D., Kool, M. n., Pfister, S. n., Hasselblatt, M. n., Frühwald, M. C., Delattre, O. n., Surdez, D. n., Bourdeaut, F. n., Puget, S. n., Zaidi, S. n., Mitra, S. S., Cheshier, S. n., Sorensen, P. H., Monje, M. n., Mackall, C. L. 2020
Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.
View details for DOI 10.1038/s41591-020-0821-8
Bespoke myelin tailored to neuron type. Science (New York, N.Y.) Yalçın, B. n., Monje, M. n. 2020; 370 (6523): 1414–15
View details for DOI 10.1126/science.abf4646
Synaptic communication in brain cancer. Cancer research Monje, M. n. 2020
Increasing evidence indicates that the nervous system plays a critical role in cancer progression. This is particularly true in cancers that occur within the central nervous system. Communication between neurons and cancer cells is a fundamental component of brain cancer pathophysiology, both for primary gliomas and for brain metastases. Neuronal activity drives growth of glial malignancies through secreted growth factors and through direct electrochemical synaptic communication. Reciprocally, brain cancers influence neuronal function, increasing neuronal activity and modulating the function of the circuits into which the cancer cells structurally and electrically integrate. Advancing understanding of neuron-cancer interactions will elucidate new therapeutic strategies for these presently lethal brain cancers.
View details for DOI 10.1158/0008-5472.CAN-20-0646
Understanding the Deadly Silence of Posterior Fossa A Ependymoma. Molecular cell Lin, G. L., Monje, M. n. 2020; 78 (6): 999–1001
In a breakthrough study in a recent issue of Cell, Michealraj et al. (2020) demonstrate that posterior fossa A ependymoma, a lethal pediatric brain tumor with a silent genome, is dependent upon metabolic changes associated with hypoxia that drive the tumor's characteristic epigenetic dysregulation.
View details for DOI 10.1016/j.molcel.2020.05.020
Treating cancer therapy-related cognitive impairment. Nature medicine Gibson, E. M., Monje, M. n. 2020
NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings. Neuro-oncology advances Theeler, B. J., Dalal, Y. n., Monje, M. n., Shilatifard, A. n., Suvà, M. L., Aboud, O. n., Camphausen, K. n., Cordova, C. n., Finch, E. n., Heiss, J. D., Packer, R. J., Romo, C. G., Aldape, K. n., Penas-Prado, M. n., Armstrong, T. n., Gilbert, M. R. 2020; 2 (1): vdaa007
Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 (H3F3A gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the H3F3A gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.
View details for DOI 10.1093/noajnl/vdaa007
Monosynaptic tracing maps brain-wide afferent oligodendrocyte precursor cell connectivity. eLife Mount, C. W., Yalcin, B., Cunliffe-Koehler, K., Sundaresh, S., Monje, M. 2019; 8
Neurons form bona fide synapses with oligodendrocyte precursor cells (OPCs), but the circuit context of these neuron to OPC synapses remains incompletely understood. Using monosynaptically-restricted rabies virus tracing of OPC afferents, we identified extensive afferent synaptic inputs to OPCs residing in secondary motor cortex, corpus callosum, and primary somatosensory cortex of adult mice. These inputs primarily arise from functionally-interconnecting cortical areas and thalamic nuclei, illustrating that OPCs have strikingly comprehensive synaptic access to brain-wide projection networks. Quantification of these inputs revealed excitatory and inhibitory components that are consistent in number across brain regions and stable in barrel cortex despite whisker trimming-induced sensory deprivation.
Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State. Molecular cell Nagaraja, S., Quezada, M. A., Gillespie, S. M., Arzt, M., Lennon, J. J., Woo, P. J., Hovestadt, V., Kambhampati, M., Filbin, M. G., Suva, M. L., Nazarian, J., Monje, M. 2019
Development of effective targeted cancer therapies is fundamentally limited by our molecular understanding of disease pathogenesis. Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique substitution to methionine in histone H3 at lysine 27 (H3K27M) that results in globally altered epigenetic marks and oncogenic transcription. Through primary DIPG tumor characterization and isogenic oncohistone expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending upon both the variant of histone H3 and the cell context in which the mutation occurs. Compared with non-malignant pediatric pontine tissue, we identify and functionally validate both shared and variant-specific pathophysiology. Altogether, we provide a powerful resource of epigenomic data in 25 primary DIPG samples and 5 rare normal pediatric pontine tissue samples, revealing clinically relevant functional distinctions previously unidentified in DIPG.
Diffuse intrinsic pontine glioma: molecular landscape and emerging therapeutic targets. Current opinion in oncology Aziz-Bose, R., Monje, M. 2019
PURPOSE OF REVIEW: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem malignancy. Despite advances in understanding of the molecular underpinnings of the tumor in the past decade, the dismal prognosis of DIPG has thus far remained unchanged. This review seeks to highlight promising therapeutic targets within three arenas: DIPG cell-intrinsic vulnerabilities, immunotherapeutic approaches to tumor clearance, and microenvironmental dependencies that promote tumor growth.RECENT FINDINGS: Promising therapeutic strategies from recent studies include epigenetic modifying agents such as histone deacetylase inhibitors, bromodomain and extra-terminal motif bromodomain inhibitors, and CDK7 inhibitors. Tumor-specific immunotherapies are emerging. Key interactions between DIPG and normal brain cells are coming to light, and targeting critical microenvironmental mechanisms driving DIPG growth in the developing childhood brain represents a new direction for therapy.SUMMARY: Several strategies are being evaluated in early clinical trials. However, we suspect that a multifaceted therapeutic approach utilizing cell-intrinsic, microenvironmental, and immunotherapeutic targets will be necessary for eradicating DIPG.
View details for DOI 10.1097/CCO.0000000000000577
Emerging mechanistic underpinnings and therapeutic targets for chemotherapy-related cognitive impairment. Current opinion in oncology Gibson, E. M., Monje, M. 2019
PURPOSE OF REVIEW: Modern innovations in cancer therapy have dramatically increased the number of cancer survivors. An unfortunately frequent side-effect of cancer treatment is enduring neurological impairment. Persistent deficits in attention, concentration, memory, and speed of information processing afflict a substantial fraction of cancer survivors following completion of these life-saving therapies. Here, we highlight chemotherapy-related cognitive impairment (CRCI) and discuss the current understanding of mechanisms underlying CRCI.RECENT FINDINGS: New studies emphasize the deleterious impact of chemotherapeutic agents on glial-glial and neuron-glial interactions that shape the form, function and plasticity of the central nervous system. An emerging theme in cancer therapy-related cognitive impairment is therapy-induced microglial activation and consequent dysfunction of both neural precursor cells and mature neural cell types. Recent work has highlighted the complexity of dysregulated intercellular interactions involving oligodendrocyte lineage cells, microglia, astrocytes, and neurons following exposure to traditional cancer therapies such as methotrexate. This new understanding of the mechanistic underpinnings of CRCI has elucidated potential therapeutic interventions, including colony-stimulating factor 1 receptor inhibition, TrkB agonism, and aerobic exercise.SUMMARY: Traditional cancer therapies induce lasting alterations to multiple neural cell types. Therapy-induced microglial activation is a critical component of the cause of CRCI, contributing to dysregulation of numerous processes of neural plasticity. Therapeutic targeting of microglial activation or the consequent dysregulation of neural plasticity mechanisms are emerging.
Comment on "Genetic and genomic alterations differentially dictate low-grade glioma growth through cancer stem cell-specific chemokine recruitment of T cells and microglia", Guo et al. 2019, Neuro-Oncology. Neuro-oncology Arzt, M., Monje, M. 2019
View details for DOI 10.1093/neuonc/noz125
Diffuse Intrinsic Pontine Glioma: From Diagnosis to Next-Generation Clinical Trials. Current treatment options in neurology Vitanza, N. A., Monje, M. 2019; 21 (8): 37
PURPOSE OF REVIEW: This review of diffuse intrinsic pontine glioma (DIPG) provides clinical background, a systematic approach to diagnosis and initial care, and synthesizes historical, modern, and future directions for treatment. We present evidence supporting neurosurgical biopsy, early palliative care involvement, limitation of glucocorticoid use, and the leveraging of preclinical DIPG models as a pipeline to next-generation clinical trials.RECENT FINDINGS: New molecular understanding of pediatric high-grade gliomas has led to the reclassification of DIPG as one member of a family of diffuse gliomas occurring in the midline of the central nervous system that exhibit pathognomonic mutations in genes encoding histone 3 (H3 K27M). DIPG remains a clinically relevant term, though diagnostically the 80% of DIPG cases that exhibit the H3 K27M mutation have been reclassified as diffuse midline glioma, H3 K27M-mutant. Re-irradiation has been shown to be well-tolerated and of potential benefit. Epigenetic targeting of transcriptional dependencies in preclinical models is fueling molecularly targeted clinical trials. Chimeric antigen receptor T cell immunotherapy has also demonstrated efficacy in preclinical models and provides a promising new clinical strategy. DIPG is a universally fatal, epigenetically driven tumor of the pons that is considered part of a broader class of diffuse midline gliomas sharing H3 K27M mutations. Radiation remains the standard of care, single-agent temozolomide is not recommended, and glucocorticoids should be used only sparingly. A rapid evolution of understanding in the chromatin, signaling, and immunological biology of DIPG may soon result in clinical breakthroughs.
An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma. Cell Neftel, C., Laffy, J., Filbin, M. G., Hara, T., Shore, M. E., Rahme, G. J., Richman, A. R., Silverbush, D., Shaw, M. L., Hebert, C. M., Dewitt, J., Gritsch, S., Perez, E. M., Gonzalez Castro, L. N., Lan, X., Druck, N., Rodman, C., Dionne, D., Kaplan, A., Bertalan, M. S., Small, J., Pelton, K., Becker, S., Bonal, D., Nguyen, Q., Servis, R. L., Fung, J. M., Mylvaganam, R., Mayr, L., Gojo, J., Haberler, C., Geyeregger, R., Czech, T., Slavc, I., Nahed, B. V., Curry, W. T., Carter, B. S., Wakimoto, H., Brastianos, P. K., Batchelor, T. T., Stemmer-Rachamimov, A., Martinez-Lage, M., Frosch, M. P., Stamenkovic, I., Riggi, N., Rheinbay, E., Monje, M., Rozenblatt-Rosen, O., Cahill, D. P., Patel, A. P., Hunter, T., Verma, I. M., Ligon, K. L., Louis, D. N., Regev, A., Bernstein, B. E., Tirosh, I., Suva, M. L. 2019
Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.
The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models. Nature communications Martinez-Velez, N., Garcia-Moure, M., Marigil, M., Gonzalez-Huarriz, M., Puigdelloses, M., Gallego Perez-Larraya, J., Zalacain, M., Marrodan, L., Varela-Guruceaga, M., Laspidea, V., Aristu, J. J., Ramos, L. I., Tejada-Solis, S., Diez-Valle, R., Jones, C., Mackay, A., Martinez-Climent, J. A., Garcia-Barchino, M. J., Raabe, E., Monje, M., Becher, O. J., Junier, M. P., El-Habr, E. A., Chneiweiss, H., Aldave, G., Jiang, H., Fueyo, J., Patino-Garcia, A., Gomez-Manzano, C., Alonso, M. M. 2019; 10 (1): 2235
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors CLINICAL CANCER RESEARCH Majzner, R. G., Theruvath, J. L., Nellan, A., Heitzeneder, S., Cui, Y., Mount, C. W., Rietberg, S. P., Linde, M. H., Xu, P., Rota, C., Sotillo, E., Labanieh, L., Lee, D. W., Orentas, R. J., Dimitrov, D. S., Zhu, Z., St Croix, B., Delaidelli, A., Sekunova, A., Bonvini, E., Mitra, S. S., Quezado, M. M., Majeti, R., Monje, M., Sorensen, P. B., Maris, J. M., Mackall, C. L. 2019; 25 (8): 2560–74
View details for DOI 10.1158/1078-0432.CCR-18-0432
Developmental origins and emerging therapeutic opportunities for childhood cancer. Nature medicine Filbin, M., Monje, M. 2019
Cancer is the leading disease-related cause of death in children in developed countries. Arising in the context of actively growing tissues, childhood cancers are fundamentally diseases of dysregulated development. Childhood cancers exhibit a lower overall mutational burden than adult cancers, and recent sequencing studies have revealed that the genomic events central to childhood oncogenesis include mutations resulting in broad epigenetic changes or translocations that result in fusion oncoproteins. Here, we will review the developmental origins of childhood cancers, epigenetic dysregulation in tissue stem/precursor cells in numerous examples of childhood cancer oncogenesis and emerging therapeutic opportunities aimed at both cell-intrinsic and microenvironmental targets together with new insights into the mechanisms underlying long-term sequelae of childhood cancer therapy.
Developmental origins and emerging therapeutic opportunities for childhood cancer NATURE MEDICINE Filbin, M., Monje, M. 2019; 25 (3): 367–76
CAR T cells targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research Majzner, R. G., Theruvath, J. L., Nellan, A., Heitzeneder, S., Cui, Y., Mount, C. W., Rietberg, S. P., Linde, M. H., Xu, P., Rota, C., Sotillo, E., Labanieh, L., Lee, D. W., Orentas, R. J., Dimitrov, D. S., Zhu, Z., St Croix, B., Delaidelli, A., Sekunova, A., Bonvini, E., Mitra, S. S., Quezado, M. M., Majeti, R., Monje, M., Sorensen, P. H., Maris, J. M., Mackall, C. L. 2019
PURPOSE: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T cell therapy of pediatric solid tumors, including those arising in the central nervous system.EXPERIMENTAL DESIGN: We developed a novel B7-H3 CAR whose binder is derived from a monoclonal antibody that has been shown to preferentially bind tumor tissues and has been safely used in humans in early phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.RESULTS: B7-H3 CAR T cells mediate significant anti-tumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.CONCLUSIONS: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies which should be tested in carefully designed clinical trials.
Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Science translational medicine Lin, G. L., Wilson, K. M., Ceribelli, M. n., Stanton, B. Z., Woo, P. J., Kreimer, S. n., Qin, E. Y., Zhang, X. n., Lennon, J. n., Nagaraja, S. n., Morris, P. J., Quezada, M. n., Gillespie, S. M., Duveau, D. Y., Michalowski, A. M., Shinn, P. n., Guha, R. n., Ferrer, M. n., Klumpp-Thomas, C. n., Michael, S. n., McKnight, C. n., Minhas, P. n., Itkin, Z. n., Raabe, E. H., Chen, L. n., Ghanem, R. n., Geraghty, A. C., Ni, L. n., Andreasson, K. I., Vitanza, N. A., Warren, K. E., Thomas, C. J., Monje, M. n. 2019; 11 (519)
Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.
View details for DOI 10.1126/scitranslmed.aaw0064
International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma JOURNAL OF NEURO-ONCOLOGY Tsoli, M., Shen, H., Mayoh, C., Franshaw, L., Ehteda, A., Upton, D., Carvalho, D., Vinci, M., Meel, M. H., van Vuurden, D., Plessier, A., Castel, D., Drissi, R., Farrell, M., Cryan, J., Crimmins, D., Caird, J., Pears, J., Francis, S., Ludlow, L. A., Carai, A., Mastronuzzi, A., Liu, B., Hansford, J., Gottardo, N., Hassall, T., Kirby, M., Fouladi, M., Hawkins, C., Monje, M., Grill, J., Jones, C., Hulleman, E., Ziegler, D. S. 2019; 141 (2): 253–63
ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma. Communications biology Carvalho, D., Taylor, K. R., Olaciregui, N. G., Molinari, V., Clarke, M., Mackay, A., Ruddle, R., Henley, A., Valenti, M., Hayes, A., Brandon, A. D., Eccles, S. A., Raynaud, F., Boudhar, A., Monje, M., Popov, S., Moore, A. S., Mora, J., Cruz, O., Vinci, M., Brennan, P. E., Bullock, A. N., Carcaboso, A. M., Jones, C. 2019; 2: 156
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.
Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult Mice. Neuron Steadman, P. E., Xia, F. n., Ahmed, M. n., Mocle, A. J., Penning, A. R., Geraghty, A. C., Steenland, H. W., Monje, M. n., Josselyn, S. A., Frankland, P. W. 2019
The generation of myelin-forming oligodendrocytes persists throughout life and is regulated by neural activity. Here we tested whether experience-driven changes in oligodendrogenesis are important for memory consolidation. We found that water maze learning promotes oligodendrogenesis and de novo myelination in the cortex and associated white matter tracts. Preventing these learning-induced increases in oligodendrogenesis without affecting existing oligodendrocytes impaired memory consolidation of water maze, as well as contextual fear, memories. These results suggest that de novo myelination tunes activated circuits, promoting coordinated activity that is important for memory consolidation. Consistent with this, contextual fear learning increased the coupling of hippocampal sharp wave ripples and cortical spindles, and these learning-induced increases in ripple-spindle coupling were blocked when oligodendrogenesis was suppressed. Our results identify a non-neuronal form of plasticity that remodels hippocampal-cortical networks following learning and is required for memory consolidation.
ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma. Communications biology Carvalho, D. n., Taylor, K. R., Olaciregui, N. G., Molinari, V. n., Clarke, M. n., Mackay, A. n., Ruddle, R. n., Henley, A. n., Valenti, M. n., Hayes, A. n., Brandon, A. D., Eccles, S. A., Raynaud, F. n., Boudhar, A. n., Monje, M. n., Popov, S. n., Moore, A. S., Mora, J. n., Cruz, O. n., Vinci, M. n., Brennan, P. E., Bullock, A. N., Carcaboso, A. M., Jones, C. n. 2019; 2 (1): 156
Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.
c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature Lynn, R. C., Weber, E. W., Sotillo, E. n., Gennert, D. n., Xu, P. n., Good, Z. n., Anbunathan, H. n., Lattin, J. n., Jones, R. n., Tieu, V. n., Nagaraja, S. n., Granja, J. n., de Bourcy, C. F., Majzner, R. n., Satpathy, A. T., Quake, S. R., Monje, M. n., Chang, H. Y., Mackall, C. L. 2019
Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer1-3, but dysfunction due to T cell exhaustion is an important barrier to progress4-6. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion6. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells7-10. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.
View details for DOI 10.1038/s41586-019-1805-z
International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma. Journal of neuro-oncology Tsoli, M., Shen, H., Mayoh, C., Franshaw, L., Ehteda, A., Upton, D., Carvalho, D., Vinci, M., Meel, M. H., van Vuurden, D., Plessier, A., Castel, D., Drissi, R., Farrell, M., Cryan, J., Crimmins, D., Caird, J., Pears, J., Francis, S., Ludlow, L. E., Carai, A., Mastronuzzi, A., Liu, B., Hansford, J., Gottardo, N., Hassall, T., Kirby, M., Fouladi, M., Hawkins, C., Monje, M., Grill, J., Jones, C., Hulleman, E., Ziegler, D. S. 2018
PURPOSE: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models.METHODS: To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development.RESULTS: In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%).CONCLUSION: This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.
Open questions: why are babies rarely born with cancer? BMC BIOLOGY Monje, M. 2018; 16
Open questions: why are babies rarely born with cancer? BMC biology Monje, M. 2018; 16 (1): 129
Childhood cancer is fundamentally a disease of dysregulated development. Why does it rarely occur during the fetal period, a time of enormous growth and development?
An active role for neurons in glioma progression: making sense of Scherer's structures NEURO-ONCOLOGY Gillespie, S., Monje, M. 2018; 20 (10): 1292–99
View details for DOI 10.1093/neuonc/noy083
Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells NATURE MEDICINE Vinci, M., Burford, A., Molinari, V., Kessler, K., Popov, S., Clarke, M., Taylor, K. R., Pemberton, H. N., Lord, C. J., Gutteridge, A., Forshew, T., Carvalho, D., Marshall, L., Qin, E. Y., Ingram, W. J., Moore, A. S., Ng, H., Trabelsi, S., Hmida-Ben Brahim, D., Entz-Werle, N., Zacharoulis, S., Vaidya, S., Mandeville, H. C., Bridges, L. R., Martin, A. J., Al-Sarraj, S., Chandler, C., Sunol, M., Mora, J., de Torres, C., Cruz, O., Carcaboso, A. M., Monje, M., Mackay, A., Jones, C. 2018; 24 (8): 1204-+
The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.
Myelin Plasticity and Nervous System Function. Annual review of neuroscience Monje, M. 2018; 41: 61–76
Structural plasticity in the myelinated infrastructure of the nervous system has come to light. Although an innate program of myelin development proceeds independent of nervous system activity, a second mode of myelination exists in which activity-dependent, plastic changes in myelin-forming cells influence myelin structure and neurological function. These complementary and possibly temporally overlapping activity-independent and activity-dependent modes of myelination crystallize in a model of experience-modulated myelin development and plasticity with broad implications for neurological function. In this article, I consider the contributions of myelin to neural circuit function, the dynamic influences of experience on myelin microstructure, and the role that plasticity of myelin may play in cognition.
Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma. Acta neuropathologica communications Lin, G. L., Nagaraja, S., Filbin, M. G., Suva, M. L., Vogel, H., Monje, M. 2018; 6 (1): 51
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9-11months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult high-grade gliomas. Thus, we directly compared inflammatory characteristics of DIPG and adult glioblastoma (GBM). We found that the leukocyte (CD45+) compartment in primary DIPG tissue samples is predominantly composed of CD11b+macrophages, with very few CD3+ T-lymphocytes. In contrast, T-lymphocytes are more abundant in adult GBM tissue samples. RNA sequencing of macrophages isolated from primary tumor samples revealed that DIPG- and adult GBM-associated macrophages both express gene programs related to ECM remodeling and angiogenesis, but DIPG-associated macrophages express substantially fewer inflammatory factors than their adult GBM counterparts. Examining the secretome of glioma cells, we found that patient-derived DIPG cell cultures secrete markedly fewer cytokines and chemokines than patient-derived adult GBM cultures. Concordantly, bulk and single-cell RNA sequencing data indicates low to absent expression of chemokines and cytokines in DIPG. Together, these observations suggest that the inflammatory milieu of the DIPG tumor microenvironment is fundamentally different than adult GBM. The low intrinsic inflammatory signature of DIPG cells may contribute to the lack of lymphocytes and non-inflammatory phenotype of DIPG-associated microglia/macrophages. Understanding the glioma subtype-specific inflammatory milieu may inform the design and application of immunotherapy-based treatments.
Non-inflammatory tumor microenvironment of diffuse intrinsic pontine glioma ACTA NEUROPATHOLOGICA COMMUNICATIONS Lin, G. L., Nagaraja, S., Filbin, M. G., Suva, M. L., Vogel, H., Monje, M. 2018; 6
A PHASE 1 TRIAL OF THE HISTONE DEACETYLASE INHIBITOR PANOBINOSTAT IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY DIFFUSE INTRINSIC PONTINE GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY Cooney, T., Onar-Thomas, A., Huang, J., Lulla, R., Fangusaro, J., Kramer, K., Baxter, P., Fouladi, M., Dunkel, I. J., Warren, K. E., Monje, M. OXFORD UNIV PRESS INC. 2018: 53
An Active Role for Neurons in Glioma Progression: Making Sense of Scherer's Structures. Neuro-oncology Gillespie, S., Monje, M. 2018
Perineuronal satellitosis, the microanatomical clustering of glioma cells around neurons in the tumor microenvironment, has been recognized as a histopathological hallmark of high-grade gliomas since the seminal observations of Scherer in the 1930s. In this review, we explore the emerging understanding that neuron - glioma cell interactions regulate malignancy, and that neuronal activity is a critical determinant of glioma growth and progression. Elucidation of the interplay between normal and malignant neural circuitry is critical to realizing the promise of effective therapies for these seemingly intractable diseases. Here, we review current knowledge regarding the role of neuronal activity in the glioma microenvironment and highlight critical knowledge gaps in this burgeoning research space.
Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq SCIENCE Filbin, M. G., Tirosh, I., Hovestadt, V., Shaw, M. L., Escalante, L. E., Mathewson, N. D., Neftel, C., Frank, N., Pelton, K., Hebert, C., Haberler, C., Yizhak, K., Gojo, J., Egervari, K., Mount, C., van Galen, P., Bonal, D. M., Quang-De Nguyen, Beck, A., Sinai, C., Czech, T., Dorfer, C., Goumnerova, L., Lavarino, C., Carcaboso, A. M., Mora, J., Mylvaganam, R., Luo, C. C., Peyrl, A., Popovic, M., Azizi, A., Batchelor, T. T., Frosch, M. P., Martinez-Lage, M., Kieran, M. W., Bandopadhayay, P., Beroukhim, R., Fritsch, G., Getz, G., Rozenblatt-Rosen, O., Wucherpfennig, K. W., Louis, D. N., Monje, M., Slavc, I., Ligon, K. L., Golub, T. R., Regev, A., Bernstein, B. E., Suva, M. L. 2018; 360 (6386): 331–35
Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.
Bad wrap: Myelin and myelin plasticity in health and disease DEVELOPMENTAL NEUROBIOLOGY Gibson, E. M., Geraghty, A. C., Monje, M. 2018; 78 (2): 123–35
Human central nervous system myelin development extends well into the fourth decade of life, and this protracted period underscores the potential for experience to modulate myelination. The concept of myelin plasticity implies adaptability in myelin structure and function in response to experiences during development and beyond. Mounting evidence supports this concept of neuronal activity-regulated changes in myelin-forming cells, including oligodendrocyte precursor cell proliferation, oligodendrogenesis and modulation of myelin microstructure. In healthy individuals, myelin plasticity in associative white matter structures of the brain is implicated in learning and motor function in both rodents and humans. Activity-dependent changes in myelin-forming cells may influence the function of neural networks that depend on the convergence of numerous neural signals on both a temporal and spatial scale. However, dysregulation of myelin plasticity can disadvantageously alter myelin microstructure and result in aberrant circuit function or contribute to pathological cell proliferation. Emerging roles for myelin plasticity in normal neurological function and in disease are discussed. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 123-135, 2018.
Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell Gibson, E. M., Nagaraja, S. n., Ocampo, A. n., Tam, L. T., Wood, L. S., Pallegar, P. N., Greene, J. J., Geraghty, A. C., Goldstein, A. K., Ni, L. n., Woo, P. J., Barres, B. A., Liddelow, S. n., Vogel, H. n., Monje, M. n. 2018
Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment.
Myelin Plasticity and Nervous System Function ANNUAL REVIEW OF NEUROSCIENCE, VOL 41 Monje, M., Roska, B., Zoghbi, H. Y. 2018; 41: 61–76
Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nature medicine Mount, C. W., Majzner, R. G., Sundaresh, S. n., Arnold, E. P., Kadapakkam, M. n., Haile, S. n., Labanieh, L. n., Hulleman, E. n., Woo, P. J., Rietberg, S. P., Vogel, H. n., Monje, M. n., Mackall, C. L. 2018
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.
Neuronal activity in the glioma microenvironment CURRENT OPINION IN NEUROBIOLOGY Johung, T., Monje, M. 2017; 47: 156–61
Gliomas are the most common primary brain tumor and high-grade gliomas the leading cause of brain tumor-related death in both children and adults. An appreciation for the crucial role of the nervous system in the tumor microenvironment is emerging for cancers in general, and the neural regulation of glioma progression has come into sharp focus. Here, we review what is known about the influence of active neurons on glioma pathobiology.
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma CANCER CELL Mackay, A., Burford, A., Carvalho, D., Izquierdo, E., Fazal-Salom, J., Taylor, K. R., Bjerke, L., Clarke, M., Vinci, M., Nandhabalan, M., Temelso, S., Popov, S., Molinari, V., Raman, P., Waanders, A. J., Han, H. J., Gupta, S., Marshall, L., Zacharoulis, S., Vaidya, S., Mandeville, H. C., Bridges, L. R., Martin, A. J., Al-Sarraj, S., Chandler, C., Ng, H., Li, X., Mu, K., Trabelsi, S., H'mida-Ben Brahim, D., Kisljakov, A. N., Konovalov, D. M., Moore, A. S., Montero Carcaboso, A., Sunol, M., de Torres, C., Cruz, O., Mora, J., Shats, L. I., Stavale, J. N., Bidinotto, L. T., Reis, R. M., Entz-Werle, N., Farrell, M., Cryan, J., Crimmins, D., Caird, J., Pears, J., Monje, M., Debily, M., Castel, D., Grill, J., Hawkins, C., Nikbakht, H., Jabado, N., Baker, S. J., Pfister, S. M., Jones, D. W., Fouladi, M., von Bueren, A. O., Baudis, M., Resnick, A., Jones, C. 2017; 32 (4): 520-+
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.
Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study NEURO-ONCOLOGY Cooney, T., Lane, A., Bartels, U., Bouffet, E., Goldman, S., Leary, S. S., Foreman, N. K., Packer, R. J., Broniscer, A., Minturn, J. E., Shih, C., Chintagumpala, M., Hassall, T., Gottardo, N. G., Dholaria, H., Hoffman, L., Chaney, B., Baugh, J., Doughman, R., Leach, J. L., Jones, B. V., Fouladi, M., Warren, K. E., Monje, M. 2017; 19 (9): 1279–80
Wrapped to Adapt: Experience-Dependent Myelination NEURON Mount, C. W., Monje, M. 2017; 95 (4): 743–56
Activity of the nervous system has long been recognized as a critical modulator of brain structure and function. Influences of experience on the cytoarchitecture and functional connectivity of neurons have been appreciated since the classic work of Hubel and Wiesel (1963; Wiesel and Hubel, 1963a, 1963b). In recent years, a similar structural plasticity has come to light for the myelinated infrastructure of the nervous system. While an innate program of myelin development proceeds independently of nervous system activity, increasing evidence supports a role for activity-dependent, plastic changes in myelin-forming cells that influence myelin structure and neurological function. Accumulating evidence of complementary and likely temporally overlapping activity-independent and activity-dependent modes of myelination are beginning to crystallize in a model of myelin plasticity, with broad implications for neurological function in health and disease.
Chemoradiation impairs normal developmental cortical thinning in medulloblastoma. Journal of neuro-oncology Kundu, P., Li, M. D., Durkee, B. Y., Hiniker, S. M., Bush, K., von Eyben, R., Monje, M. L., Yeom, K. W., Donaldson, S. S., Gibbs, I. C. 2017
Medulloblastoma patients are treated with surgery, radiation and chemotherapy. Radiation dose to the temporal lobe may be associated with neurocognitive sequelae. Longitudinal changes of temporal lobe cortical thickness may result from neurodevelopmental processes such as synaptic pruning. This study applies longitudinal image analysis to compare developmental change in cortical thickness in medulloblastoma (MB) patients who were treated by combined modality therapy to that of cerebellar juvenile pilocytic astrocytoma (JPA) patients who were treated by surgery alone. We hypothesized that the rates of developmental change in cortical thickness would differ between these two groups. This retrospective cohort study assessed changes in cortical thickness over time between MB and JPA patients. High-resolution magnetic resonance (MR) images of 14 MB and 7 JPA subjects were processed to measure cortical thickness of bilateral temporal lobe substructures. A linear mixed effects model was used to identify differences in substructure longitudinal changes in cortical thickness. The left temporal lobe exhibited overall increased cortical thickness in MB patients relative to JPA patients who showed overall cortical thinning (mean annual cortical thickness change: MB 0.14 mm/year versus JPA -0.018 mm/year across all substructures), particularly in the inferior temporal lobe substructures (p < 0.0001). The cortical thickness change of the right temporal lobe substructures exhibited similar, though attenuated trends (p = 0.002). MB patients exhibit overall increased cortical thickness rather than cortical thinning as seen in JPA patients and as expected in normal cortical development. These observations are possibly due to chemoradiation induced-disruption of normal neuronal mechanisms. Longitudinal image analysis may identify early biomarkers for neurocognitive function with routine imaging.
Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma CANCER CELL Nagaraja, S., Vitanza, N. A., Woo, P. J., Taylor, K. R., Liu, F., Zhang, L., Li, M., Meng, W., Ponnuswami, A., Sun, W., Ma, J., Hulleman, E., Swigut, T., Wysocka, J., Tang, Y., Monje, M. 2017; 31 (5): 635-?
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.
View details for DOI 10.1016/j.ccell.2017.03.011
Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq SCIENCE Venteicher, A. S., Tirosh, I., Hebert, C., Yizhak, K., Neftel, C., Filbin, M. G., Hovestadt, V., Escalante, L. E., Shaw, M. L., Rodman, C., Gillespie, S. M., Dionne, D., Luo, C. C., Ravichandran, H., Mylvaganam, R., Mount, C., Onozato, M. L., Nahed, B. V., Wakimoto, H., Curry, W. T., Iafrate, A. J., Rivera, M. N., Frosch, M. P., Golub, T. R., Brastianos, P. K., Getz, G., Patel, A. P., Monje, M., Cahill, D. P., Rozenblatt-Rosen, O., Louis, D. N., Bernstein, B. E., Regev, A., Suva, M. L. 2017; 355 (6332): 1391-?
Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.
View details for DOI 10.1126/science.aai8478
Disrupting the CD47-SIRP alpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors SCIENCE TRANSLATIONAL MEDICINE Gholamin, S., Mitra, S. S., Feroze, A. H., Liu, J., Kahn, S. A., Zhang, M., Esparza, R., Richard, C., Ramaswamy, V., Remke, M., Volkmer, A. K., Willingham, S., Ponnuswami, A., McCarty, A., Lovelace, P., Storm, T. A., Schubert, S., Hutter, G., Narayanan, C., Chu, P., Raabe, E. H., Harsh, G., Taylor, M. D., Monje, M., Cho, Y., Majeti, R., Volkmer, J. P., Fisher, P. G., Grant, G., Steinberg, G. K., Vogel, H., Edwards, M., Weissman, I. L., Cheshier, S. H. 2017; 9 (381)
Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.
View details for DOI 10.1126/scitranslmed.aaf2968
A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma (DIPG) JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Lin, G. L., Monje, M. 2017
Diffuse Intrinsic Pontine Glioma (DIPG) is a childhood brainstem tumor that carries a universally fatal prognosis. Because surgical resection is not a viable treatment strategy and biopsy is not routinely performed, the availability of patient samples for research is limited. Consequently, efforts to study this disease have been challenged by a paucity of faithful disease models. To address this need, we describe here a protocol for the rapid processing of post-mortem autopsy tissue samples in order to generate durable patient-derived cell culture models that can be used in in vitro assays or in vivo orthotopic xenograft experiments. These models can be used to screen for potential drug targets and to study fundamental pathobiological processes within DIPG. This protocol can further be extended to analyze and isolate tumor and microenvironmental cells using Fluorescence-activated Cell Sorting (FACS), which enables subsequent analysis of gene expression, protein expression, or epigenetic modifications of DNA at the bulk cell or single cell level. Finally, this protocol can also be adapted to generate patient-derived cultures for other central nervous system tumors.
View details for DOI 10.3791/55360
Brain Perfusion and Diffusion Abnormalities in Children Treated for Posterior Fossa Brain Tumors. journal of pediatrics Li, M. D., Forkert, N. D., Kundu, P., Ambler, C., Lober, R. M., Burns, T. C., Barnes, P. D., Gibbs, I. C., Grant, G. A., Fisher, P. G., Cheshier, S. H., Campen, C. J., Monje, M., Yeom, K. W. 2017
To compare cerebral perfusion and diffusion in survivors of childhood posterior fossa brain tumor with neurologically normal controls and correlate differences with cognitive dysfunction.We analyzed retrospectively arterial spin-labeled cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) in 21 patients with medulloblastoma (MB), 18 patients with pilocytic astrocytoma (PA), and 64 neurologically normal children. We generated ANCOVA models to evaluate treatment effects on the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, and cerebral white matter at time points an average of 5.7 years after original diagnosis. A retrospective review of patient charts identified 12 patients with neurocognitive data and in whom the relationship between IQ and magnetic resonance imaging variables was assessed for each brain structure.Patients with MB (all treated with surgery, chemotherapy, and radiation) had significantly lower global CBF relative to controls (10%-23% lower, varying by anatomic region, all adjusted P < .05), whereas patients with PA (all treated with surgery alone) had normal CBF. ADC was decreased specifically in the hippocampus and amygdala of patients with MB and within the amygdala of patients with PA but otherwise remained normal after therapy. In the patients with tumor previously evaluated for IQ, regional ADC, but not CBF, correlated with IQ (R(2) = 0.33-0.75).The treatment for MB, but not PA, was associated with globally reduced CBF. Treatment in both tumor types was associated with diffusion abnormalities of the mesial temporal lobe structures. Despite significant perfusion abnormalities in patients with MB, diffusion, but not perfusion, correlated with cognitive outcomes.
View details for DOI 10.1016/j.jpeds.2017.01.019
Pediatric high-grade glioma: biologically and clinically in need of new thinking NEURO-ONCOLOGY Jones, C., Karajannis, M. A., Jones, D. T., Kieran, M. W., Monje, M., Baker, S. J., Becher, O. J., Cho, Y., Gupta, N., Hawkins, C., Hargrave, D., Haas-Kogan, D. A., Jabado, N., Li, X., Mueller, S., Nicolaides, T., Packer, R. J., Persson, A. I., Phillips, J. J., Simonds, E. F., Stafford, J. M., Tang, Y., Pfister, S. M., Weiss, W. A. 2017; 19 (2): 153-161
High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.
View details for DOI 10.1093/neuonc/now101
Neuronal Activity in Ontogeny and Oncology TRENDS IN CANCER Venkatesh, H., Monje, M. 2017; 3 (2): 89–112
The nervous system plays a central role in regulating the stem cell niche in many organs, and thereby pivotally modulates development, homeostasis, and plasticity. A similarly powerful role for neural regulation of the cancer microenvironment is emerging. Neurons promote the growth of cancers of the brain, skin, prostate, pancreas, and stomach. Parallel mechanisms shared in development and cancer suggest that neural modulation of the tumor microenvironment may prove a universal theme, although the mechanistic details of such modulation remain to be discovered for many malignancies. We review here what is known about the influences of active neurons on stem cell and cancer microenvironments across a broad range of tissues, and we discuss emerging principles of neural regulation of development and cancer.
The international diffuse intrinsic pontine glioma registry: an infrastructure to accelerate collaborative research for an orphan disease. Journal of neuro-oncology Baugh, J., Bartels, U., Leach, J., Jones, B., Chaney, B., Warren, K. E., Kirkendall, J., Doughman, R., Hawkins, C., Miles, L., Fuller, C., Hassall, T., Bouffet, E., Lane, A., Hargrave, D., Grill, J., Hoffman, L. M., Jones, C., Towbin, A., Savage, S. A., Monje, M., Li, X., Ziegler, D. S., Veldhuijzen van Zanten, S., Kramm, C. M., van Vuurden, D. G., Fouladi, M. 2017
Diffuse intrinsic pontine glioma (DIPG), a rare, often fatal childhood brain tumor, remains a major therapeutic challenge. In 2012, investigators, funded by the DIPG Collaborative (a philanthropic partnership among 29 private foundations), launched the International DIPG Registry (IDIPGR) to advance understanding of DIPG. Comprised of comprehensive deidentified but linked clinical, imaging, histopathological, and genomic repositories, the IDIPGR uses standardized case report forms for uniform data collection; serial imaging and histopathology are centrally reviewed by IDIPGR neuro-radiologists and neuro-pathologists, respectively. Tissue and genomic data, and cell cultures derived from autopsies coordinated by the IDIPGR are available to investigators for studies approved by the Scientific Advisory Committee. From April 2012 to December 2016, 670 patients diagnosed with DIPG have been enrolled from 55 participating institutions in the US, Canada, Australia and New Zealand. The radiology repository contains 3558 studies from 448 patients. The pathology repository contains tissue on 81 patients with another 98 samples available for submission. Fresh DIPG tissue from seven autopsies has been sent to investigators to develop primary cell cultures. The bioinformatics repository contains next-generation sequencing data on 66 tumors. Nine projects using data/tissue from the IDIPGR by 13 principle investigators from around the world are now underway. The IDIPGR, a successful alliance among philanthropic agencies and investigators, has developed and maintained a highly collaborative, hypothesis-driven research infrastructure for interdisciplinary and translational projects in DIPG to improve diagnosis, response assessment, treatment and outcome for patients.
Settling a Nervous Stomach: The Neural Regulation of Enteric Cancer CANCER CELL Monje, M. 2017; 31 (1): 1–2
The nervous system is emerging as a regulator of malignancy. In this issue of Cancer Cell, Hayakawa et al. demonstrate a feedforward signaling loop in which tumor-derived nerve growth factor promotes enteric tumor innervation, and recruited nerves drive cancer growth through acetylcholine-regulated Wnt signaling and stimulation of further NGF release.
Diffuse Intrinsic Pontine Glioma: New Pathophysiological Insights and Emerging Therapeutic Targets CURRENT NEUROPHARMACOLOGY Johung, T. B., Monje, M. 2017; 15 (1): 88-97
Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of brain tumor-related death in children, with median survival of less than one year. Despite decades of clinical trials, there has been no improvement in prognosis since the introduction of radiotherapy over thirty years ago.To review the clinical features and current treatment challenges of DIPG, and discuss emerging insights into the unique genomic and epigenomic mechanisms driving DIPG pathogenesis that present new opportunities for the identification of therapeutic targets.In recent years, an increased availability of biopsy and rapid autopsy tissue samples for preclinical investigation has combined with the advent of new genomic and epigenomic profiling tools to yield remarkable advancements in our understanding of DIPG disease mechanisms. As well, a deeper understanding of the developmental context of DIPG is shedding light on therapeutic targets in the microenvironment of the childhood brain.
View details for DOI 10.2174/1570159X14666160509123229
Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature Tirosh, I., Venteicher, A. S., Hebert, C., Escalante, L. E., Patel, A. P., Yizhak, K., Fisher, J. M., Rodman, C., Mount, C., Filbin, M. G., Neftel, C., Desai, N., Nyman, J., Izar, B., Luo, C. C., Francis, J. M., Patel, A. A., Onozato, M. L., Riggi, N., Livak, K. J., Gennert, D., Satija, R., Nahed, B. V., Curry, W. T., Martuza, R. L., Mylvaganam, R., Iafrate, A. J., Frosch, M. P., Golub, T. R., Rivera, M. N., Getz, G., Rozenblatt-Rosen, O., Cahill, D. P., Monje, M., Bernstein, B. E., Louis, D. N., Regev, A., Suvà, M. L. 2016
Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.
View details for DOI 10.1038/nature20123
Myelin plasticity in the central nervous system. Neuropharmacology Purger, D., Gibson, E. M., Monje, M. 2016; 110: 563-573
Myelin sheaths, specialized segments of oligodendrocyte (OL) plasma membranes in the central nervous system (CNS), facilitate fast, saltatory conduction of action potentials down axons. Changes to the fine structure of myelin in a neural circuit, including sheath thickness and internode length (length of myelin segments between nodes of Ranvier), are expected to affect conduction velocity of action potentials. Myelination of the mammalian CNS occurs in a stereotyped, progressive pattern and continues well into adulthood in humans. Recent evidence from zebrafish, rodents, non-human primates, and humans suggests that myelination may be sensitive to experiences during development and adulthood, and that varying levels of neuronal activity may underlie these experience-dependent changes in myelin and myelin-forming cells. Several cellular, molecular, and epigenetic mechanisms have been investigated as contributors to myelin plasticity. A deeper understanding of myelin plasticity and its underlying mechanisms may provide insights into diseases involving myelin damage or dysregulation. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.
View details for DOI 10.1016/j.neuropharm.2015.08.001
Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro-oncology Jones, C., Karajannis, M. A., Jones, D. T., Kieran, M. W., Monje, M., Baker, S. J., Becher, O. J., Cho, Y., Gupta, N., Hawkins, C., Hargrave, D., Haas-Kogan, D. A., Jabado, N., Li, X., Mueller, S., Nicolaides, T., Packer, R. J., Persson, A. I., Phillips, J. J., Simonds, E. F., Stafford, J. M., Tang, Y., Pfister, S. M., Weiss, W. A. 2016
Neurologic Complications of Oncologic Therapy HANDBOOK OF NEURO-ONCOLOGY NEUROIMAGING, 2ND EDITION Arrillaga-Romany, I., Monje, M., Wen, P. Y., Newton, H. B. 2016: 125–42
View details for DOI 10.1016/B978-0-12-800945-1.00015-X
Functionally defined therapeutic targets in diffuse intrinsic pontine glioma NATURE MEDICINE Grasso, C. S., Tang, Y., Truffaux, N., Berlow, N. E., Liu, L., Debily, M., Quist, M. J., Davis, L. E., Huang, E. C., Woo, P. J., Ponnuswami, A., Chen, S., Johung, T. B., Sun, W., Kogiso, M., Dui, Y., Qi, L., Huang, Y., Huett-Cabezas, M., Warrenm, K. E., Le Dret, L., Meltzerm, P. S., Mao, H., Quezado, M., van Vuurden, D. G., Abraham, J., Fouladi, M., Svalina, M. N., Wang, N., Hawkins, C., Nazarian, J., Alonso, M. M., Raabe, E. H., Hulleman, E., Spellman, P. T., Li, X., Keller, C., Pal, R., Grill, J., Monje, M. 2015; 21 (6): 555-559
Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.
View details for DOI 10.1038/nm.3855
FUNCTIONAL DIVERSITY AND CO-OPERATIVITY OF SUBCLONAL POPULATIONS OF PAEDIATRIC GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA CELLS Vinci, M., Burford, A., Taylor, K., Molinari, V., Popov, S., Ingram, W., Moore, A., Monje, M., Alonso, M., Pears, J., Entz-Werle, N., de Torres, C., Cruz, O., Mora, J., Carcaboso, A., Mackay, A., Jones, C. OXFORD UNIV PRESS INC. 2015: 4
SUBVENTRICULAR SPREAD OF DIFFUSE INTRINSIC PONTINE GLIOMA Caretti, V., Bugiani, M., Freret, M., Schellen, P., Jansen, M., van Vuurden, D., Kaspers, G., Fisher, P. G., Hulleman, E., Wesseling, P., Vogel, H., Monje, M. OXFORD UNIV PRESS INC. 2014
View details for DOI 10.1093/neuonc/nou261.3
Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition NATURE MEDICINE Tang, Y., Gholamin, S., Schubert, S., Willardson, M. I., Lee, A., Bandopadhayay, P., Bergthold, G., Masoud, S., Nguyen, B., Vue, N., Balansay, B., Yu, F., Oh, S., Woo, P., Chen, S., Ponnuswami, A., Monje, M., Atwood, S. X., Whitson, R. J., Mitra, S., Cheshier, S. H., Qi, J., Beroukhim, R., Tang, J. Y., Wechsler-Reya, R., Oro, A. E., Link, B. A., Bradner, J. E., Cho, Y. 2014; 20 (7): 732-740
Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.
Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nature medicine Tang, Y., Gholamin, S., Schubert, S., Willardson, M. I., Lee, A., Bandopadhayay, P., Bergthold, G., Masoud, S., Nguyen, B., Vue, N., Balansay, B., Yu, F., Oh, S., Woo, P., Chen, S., Ponnuswami, A., Monje, M., Atwood, S. X., Whitson, R. J., Mitra, S., Cheshier, S. H., Qi, J., Beroukhim, R., Tang, J. Y., Wechsler-Reya, R., Oro, A. E., Link, B. A., Bradner, J. E., Cho, Y. 2014; 20 (7): 732-740
Human pontine glioma cells can induce murine tumors. Acta neuropathologica Caretti, V., Sewing, A. C., Lagerweij, T., Schellen, P., Bugiani, M., Jansen, M. H., van Vuurden, D. G., Navis, A. C., Horsman, I., Vandertop, W. P., Noske, D. P., Wesseling, P., Kaspers, G. J., Nazarian, J., Vogel, H., Hulleman, E., Monje, M., Wurdinger, T. 2014; 127 (6): 897-909
Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9 months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy (1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or (2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprising human cells. Of note, direct injection of cells obtained postmortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.
Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma NATURE GENETICS Taylor, K. R., Mackay, A., Truffaux, N., Butterfield, Y. S., Morozova, O., Philippe, C., Castel, D., Grasso, C. S., Vinci, M., Carvalho, D., Carcaboso, A. M., de Torres, C., Cruz, O., Mora, J., Entz-Werle, N., Ingram, W. J., Monje, M., Hargrave, D., Bullock, A. N., Puget, S., Yip, S., Jones, C., Grill, J. 2014; 46 (5): 457-461
Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.
View details for DOI 10.1038/ng.2925
Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma. Journal of neuro-oncology Lober, R. M., Cho, Y., Tang, Y., Barnes, P. D., Edwards, M. S., Vogel, H., Fisher, P. G., Monje, M., Yeom, K. W. 2014; 117 (1): 175-182
While pediatric diffuse intrinsic pontine gliomas (DIPG) remain fatal, recent data have shown subgroups with distinct molecular biology and clinical behavior. We hypothesized that diffusion-weighted MRI can be used as a prognostic marker to stratify DIPG subsets with distinct clinical behavior. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted MRI were computed in 20 consecutive children with treatment-naïve DIPG tumors. The median ADC for the cohort was used to stratify the tumors into low and high ADC groups. Survival, gender, therapy, and potential steroid effects were compared between the ADC groups. Median age at diagnosis was 6.6 (range 2.3-13.2) years, with median follow-up seven (range 1-36) months. There were 14 boys and six girls. Seventeen patients received radiotherapy, five received chemotherapy, and six underwent cerebrospinal fluid diversion. The median ADC of 1,295 × 10(-6) mm(2)/s for the cohort partitioned tumors into low or high diffusion groups, which had distinct median survivals of 3 and 13 months, respectively (log-rank p < 0.001). Low ADC tumors were found only in boys, whereas high ADC tumors were found in both boys and girls. Available tissue specimens in three low ADC tumors demonstrated high-grade histology, whereas one high ADC tumor demonstrated low-grade histology with a histone H3.1 K27M mutation and high-grade metastatic lesion at autopsy. ADC derived from diffusion-weighted MRI may identify prognostically distinct subgroups of pediatric DIPG.
Subventricular spread of diffuse intrinsic pontine glioma. Acta neuropathologica Caretti, V. n., Bugiani, M. n., Freret, M. n., Schellen, P. n., Jansen, M. n., van Vuurden, D. n., Kaspers, G. n., Fisher, P. G., Hulleman, E. n., Wesseling, P. n., Vogel, H. n., Monje, M. n. 2014
Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas. Cancer cell Bender, S., Tang, Y., Lindroth, A. M., Hovestadt, V., Jones, D. T., Kool, M., Zapatka, M., Northcott, P. A., Sturm, D., Wang, W., Radlwimmer, B., Højfeldt, J. W., Truffaux, N., Castel, D., Schubert, S., Ryzhova, M., Seker-Cin, H., Gronych, J., Johann, P. D., Stark, S., Meyer, J., Milde, T., Schuhmann, M., Ebinger, M., Monoranu, C., Ponnuswami, A., Chen, S., Jones, C., Witt, O., Collins, V. P., von Deimling, A., Jabado, N., Puget, S., Grill, J., Helin, K., Korshunov, A., Lichter, P., Monje, M., Plass, C., Cho, Y., Pfister, S. M. 2013; 24 (5): 660-672
Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ∼50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.
View details for DOI 10.1016/j.ccr.2013.10.006
Functional and structural differences in the hippocampus associated with memory deficits in adult survivors of acute lymphoblastic leukemia PEDIATRIC BLOOD & CANCER Monje, M., Thomason, M. E., Rigolo, L., Wang, Y., Waber, D. P., Sallan, S. E., Golby, A. J. 2013; 60 (2): 293-300
Radiation and chemotherapy targeted to the central nervous system (CNS) can cause cognitive impairment, including impaired memory. These memory impairments may be referable to damage to hippocampal structures resulting from CNS treatment.In the present study, we explored episodic memory and its neuroimaging correlates in 10 adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy and both systemic and intrathecal chemotherapy and 10 controls matched for age and sex, using a subsequent memory paradigm after episodic encoding of visual scenes.We report behavioral, structural, and functional changes in the brains of the adult survivors. They demonstrated poorer recognition memory, hippocampal atrophy, and altered blood oxygenation level-dependent (BOLD) signal in the hippocampus. Whole brain statistical map analysis revealed increased BOLD signal/activation in several brain regions during unsuccessful encoding in ALL survivors, potentially reflecting ineffective neural recruitment. Individual differences in memory performance in ALL participants were related to magnitude of BOLD response in regions associated with successful encoding.Taken together, these findings describe long term neuroimaging correlates of cognitive dysfunction after childhood exposure to CNS-targeted cancer therapies, suggesting enduring damage to episodic memory systems.
View details for DOI 10.1002/pbc.24263
Effect of cancer therapy on neural stem cells: implications for cognitive function CURRENT OPINION IN ONCOLOGY Gibson, E., Monje, M. 2012; 24 (6): 672-678
Modern cancer therapies have allowed for a dramatic increase in the survival rates in both children and adults. However, a frequent and unfortunate side-effect of cancer therapy is a long-term decline in neurocognitive function. Specifically, cranial radiation therapy markedly alters memory processes, while chemotherapeutic agents are correlated with deficits in attention, concentration, and speed of information processing. Here, we describe the putative cellular etiologies of cancer treatment-induced cognitive decline, with an emphasis on the role of neural stem and precursor cell dysfunction.New studies highlight the lasting effects of chemotherapy on memory, executive function, attention, and speed of information processing up to 20 years following chemotherapy. Cognitive decrements are associated with decreased white-matter integrity as well as alterations in stem cell function in humans and rodent models of cancer therapy. Genetic polymorphisms may underlie differential sensitivity of certain individuals to the neurological consequences of chemotherapy. Increasing data support the concept that disruption of normal neural stem and precursor cell function is an important causative factor for the cognitive deficits that result from cancer therapy in both children and adults.Further studies are needed to elucidate the role of chemotherapy on cell-intrinsic processes and cellular microenvironments. Further, the effects of the new generation of targeted molecular therapies on neural stem and progenitor cell function remains largely untested. Understanding the mechanisms behind cancer therapy-induced damage to neural stem and precursor cell populations will elucidate neuroprotective and cell replacement strategies aimed at preserving cognition after cancer therapy.
View details for DOI 10.1097/CCO.0b013e3283571a8e
Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis BEHAVIOURAL BRAIN RESEARCH Monje, M., Dietrich, J. 2012; 227 (2): 376-379
Cancer therapies frequently result in a spectrum of neurocognitive deficits that include impaired learning, memory, attention and speed of information processing. Damage to dynamic neural progenitor cell populations in the brain are emerging as important etiologic factors. Radiation and chemotherapy-induced damage to neural progenitor populations responsible for adult hippocampal neurogenesis and for maintenance of subcortical white matter integrity are now believed to play major roles in the neurocognitive impairment many cancer survivors experience.
View details for DOI 10.1016/j.bbr.2011.05.012
Complete Ocular Paresis in a Child with Posterior Fossa Syndrome PEDIATRIC NEUROSURGERY Afshar, M., Link, M., Edwards, M. S., Fisher, P. G., Fredrick, D., Monje, M. 2012; 48 (1): 51-54
Posterior fossa syndrome (PFS), also known as cerebellar affective syndrome, is characterized by emotional lability and decreased speech production following injury or surgery to the cerebellum. Rarely, oculomotor dysfunction has been described in association with PFS. Here, we report a case of complete ocular paresis associated with PFS in an 11-year-old male following medulloblastoma resection.
View details for DOI 10.1159/000339382
Cellular Mechanisms of Radiation Injury to Cognition NEUROLOGIC COMPLICATIONS OF CANCER THERAPY Monje, M., Wen, P. Y., Schiff, D., Lee, E. Q. 2012: 291–99
Hedgehogs, Flies, Wnts and MYCs: The Time Has Come for Many Things in Medulloblastoma JOURNAL OF CLINICAL ONCOLOGY Monje, M., Beachy, P. A., Fisher, P. G. 2011; 29 (11): 1395-1398
View details for DOI 10.1200/JCO.2010.34.0547
Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Monje, M., Mitra, S. S., Freret, M. E., Raveh, T. B., Kim, J., Masek, M., Attema, J. L., Li, G., Haddix, T., Edwards, M. S., Fisher, P. G., Weissman, I. L., Rowitch, D. H., Vogel, H., Wong, A. J., Beachy, P. A. 2011; 108 (11): 4453-4458
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.
View details for DOI 10.1073/pnas.1101657108
Neurological complications following treatment of children with brain tumors. Journal of pediatric rehabilitation medicine Monje, M., Fisher, P. G. 2011; 4 (1): 31-36
Brain tumors and their treatments in children result in a range of neurological complications that can affect daily function and rehabilitation potential, including neurocognitive sequelae, ototoxicity, seizure disorders, stroke, and peripheral neuropathy. Deficits in cognitive function, particularly learning and memory, attention and speed of information processing, can be debilitating. With new insights to the cellular and molecular etiology of these deficits, new therapies for cognitive decline after therapy are emerging. Management strategies for other neurological complications are also emerging.
View details for DOI 10.3233/PRM-2011-0150
Clinical Patterns and Biological Correlates of Cognitive Dysfunction Associated with Cancer Therapy ONCOLOGIST Dietrich, J., Monje, M., Wefel, J., Meyers, C. 2008; 13 (12): 1285-1295
Standard oncological therapies, such as chemotherapy and cranial radiotherapy, frequently result in a spectrum of neurocognitive deficits that includes impaired learning, memory, attention, and speed of information processing. In addition to classical mechanisms of neurotoxicity associated with chemo- and radiotherapy, such as radiation necrosis and leukoencephalopathy, damage to dynamic progenitor cell populations in the brain is emerging as an important etiologic factor. Radiation- and chemotherapy-induced damage to progenitor populations responsible for maintenance of white matter integrity and adult hippocampal neurogenesis is now believed to play a major role in the neurocognitive impairment many cancer survivors experience.
View details for DOI 10.1634/theoncologist.2008-0130
CRANIAL RADIATION THERAPY AND DAMAGE TO HIPPOCAMPAL NEUROGENESIS DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS Monje, M. 2008; 14 (3): 238-242
Cranial radiation therapy is associated with a progressive decline in cognitive function, prominently memory function. Impairment of hippocampal neurogenesis is thought to be an important mechanism underlying this cognitive decline. Recent work has elucidated the mechanisms of radiation-induced failure of neurogenesis. Potential therapeutic interventions are emerging.
View details for DOI 10.1002/ddrr.26
Impaired human hippocampal neurogenesis after treatment for central nervous system ANNALS OF NEUROLOGY Monje, M. L., Vogel, H., Masek, M., Ligon, K. L., Fisher, P. G., Palmer, T. D. 2007; 62 (5): 515-520
The effects of cancer treatments such as cranial radiation and chemotherapy on human hippocampal neurogenesis remain unknown. In this study, we examine neuropathological markers of neurogenesis and inflammation in the human hippocampus after treatment for acute myelogenous leukemia or medulloblastoma. We demonstrate a persistent radiation-induced microglial inflammation that is accompanied by nearly complete inhibition of neurogenesis after cancer treatment. These findings are consistent with preclinical animal studies and suggest potential therapeutic strategies.
View details for DOI 10.1002/ana.21214
Excitation-neurogenesis coupling in adult neural stem/progenitor cells NEURON Deisseroth, K., Singla, S., Toda, H., Monje, M., Palmer, T. D., Malenka, R. C. 2004; 42 (4): 535-552
A wide variety of in vivo manipulations influence neurogenesis in the adult hippocampus. It is not known, however, if adult neural stem/progenitor cells (NPCs) can intrinsically sense excitatory neural activity and thereby implement a direct coupling between excitation and neurogenesis. Moreover, the theoretical significance of activity-dependent neurogenesis in hippocampal-type memory processing networks has not been explored. Here we demonstrate that excitatory stimuli act directly on adult hippocampal NPCs to favor neuron production. The excitation is sensed via Ca(v)1.2/1.3 (L-type) Ca(2+) channels and NMDA receptors on the proliferating precursors. Excitation through this pathway acts to inhibit expression of the glial fate genes Hes1 and Id2 and increase expression of NeuroD, a positive regulator of neuronal differentiation. These activity-sensing properties of the adult NPCs, when applied as an "excitation-neurogenesis coupling rule" within a Hebbian neural network, predict significant advantages for both the temporary storage and the clearance of memories.
Inflammatory blockade restores adult hippocampal neurogenesis SCIENCE Monje, M. L., Toda, H., Palmer, T. D. 2003; 302 (5651): 1760-1765
Cranial radiation therapy causes a progressive decline in cognitive function that is linked to impaired neurogenesis. Chronic inflammation accompanies radiation injury, suggesting that inflammatory processes may contribute to neural stem cell dysfunction. Here, we show that neuroinflammation alone inhibits neurogenesis and that inflammatory blockade with indomethacin, a common nonsteroidal anti-inflammatory drug, restores neurogenesis after endotoxin-induced inflammation and augments neurogenesis after cranial irradiation.
Extreme sensitivity of adult neurogenesis to low doses of X-irradiation CANCER RESEARCH Mizumatsu, S., Monje, M. L., Morhardt, D. R., Rola, R., Palmer, T. D., Fike, J. R. 2003; 63 (14): 4021-4027
Therapeutic irradiation of the brain is associated with a number of adverse effects, including cognitive impairment. Although the pathogenesis of radiation-induced cognitive injury is unknown, it may involve loss of neural precursor cells from the subgranular zone (SGZ) of the hippocampal dentate gyrus and alterations in new cell production (neurogenesis). Young adult male C57BL mice received whole brain irradiation, and 6-48 h later, hippocampal tissue was assessed using immunohistochemistry for detection of apoptosis and numbers of proliferating cells and immature neurons. Apoptosis peaked 12 h after irradiation, and its extent was dose dependent. Forty-eight h after irradiation, proliferating SGZ cells were reduced by 93-96%; immature neurons were decreased from 40 to 60% in a dose-dependent fashion. To determine whether acute cell sensitivity translated into long-term changes, we quantified neurogenesis 2 months after irradiation with 0, 2, 5, or 10 Gy. Multiple injections of BrdUrd were given to label proliferating cells, and 3 weeks later, confocal microscopy was used to determine the percentage of BrdUrd-labeled cells that showed mature cell phenotypes. The production of new neurons was significantly reduced by X-rays; that change was dose dependent. In contrast, there were no apparent effects on the production of new astrocytes or oligodendrocytes. Measures of activated microglia indicated that changes in neurogenesis were associated with a significant inflammatory response. Given the known effects of radiation on cognitive function and the relationship between hippocampal neurogenesis and associated memory formation, our data suggest that precursor cell radiation response and altered neurogenesis may play a contributory if not causative role in radiation-induced cognitive impairment.
Radiation injury and neurogenesis CURRENT OPINION IN NEUROLOGY Monje, M. L., Palmer, T. 2003; 16 (2): 129-134
For many cancers, survival depends on aggressive combined therapies, but treatment comes at a price. Children and adults who receive radiotherapy involving the brain frequently experience a progressive cognitive decline. The overt pathologies of radiation injury such as white matter necrosis or vasculopathy are the obvious "smoking guns" of dysfunction. However, many patients exhibit severe learning and memory deficits with no overt pathologic changes. This is especially true when the radiation field involves the temporal lobes. The cause of this debilitating dysfunction is currently unknown and untreatable.Within the temporal lobe, the hippocampal formation plays a central role in short-term learning and memory--the functions most notably affected by radiation. Recent work has also shown that hippocampus-dependent learning and memory are strongly influenced by the activity of neural stem cells and their proliferative progeny. The hippocampal granule cell layer undergoes continuous renewal and restructuring by the addition of new neurons. Radiation at much lower doses than that needed to injure the more resistant post-mitotic neurons and glia of the brain has been found to affect these highly proliferative progenitors severely. The stem/progenitor cell is so sensitive to radiation that a single low dose to the cranium of a mature rat is sufficient to ablate hippocampal neurogenesis.Progressive learning and memory deficits following irradiation may be caused by the accumulating hippocampal dysfunction that results from a long-term absence of normal stem/progenitor activity. Here, the authors describe the nature of this stem cell dysfunction and contemplate how restoration of stem/progenitor cell activity might be approached in experimental models and, eventually, the clinic.
View details for DOI 10.1097/01.wco.0000063772.8181.b7
Irradiation induces neural precursor-cell dysfunction NATURE MEDICINE Monje, M. L., Mizumatsu, S., Fike, J. R., Palmer, T. D. 2002; 8 (9): 955-962
In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.
View details for DOI 10.1038/nm749

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