In conclusion, this study examines a specific sensor of the tumor microenvironment, the integrin α6β4, and provides an exciting new role for this molecule in promoting tumor progression. Our data offer a novel mechanism for the upregulation of tumor promoting genes, alterations in the epigenome, and utilization of DNA repair, and places the integrin α6β4 as a major player in cancer epigenetics. These findings have far reaching impacts on our understanding of pancreatic carcinoma and further analysis of the integrin α6β4’s role in these processes will yield a more comprehensive understanding for how this integrin impacts tumor progression.