Using exome sequencing approaches, recent studies have identified multiple genetic modifications in human HB samples, including gain-of-function mutations of CTNNB1 and CAPRIN2, and loss-of-function mutations of Axin1 and SPOP . Among them, mutations of CTNNB1 and CAPRIN2 genes lead to the activation of the canonical Wnt pathway, a major driver genetic event promoting HB development [6, 7]. Point mutations as well as in-frame deletions of the exon 3 in CTNNB1 gene have been detected in ∼80% of human HB patients. These mutations lead to stabilization, nuclear localization, and activation of β-catenin transcriptional activity, with consequent induction of a large number of target genes involved in proliferation, survival, migration, and invasion [8, 9]. It is important to underline that while β-catenin cascade is essential for HB development , over-expression of either full length, N-terminal deleted mutation (ΔN90), or point mutation (S45Y) forms of β-catenin alone is not sufficient to promote HB formation in mice. This evidence suggests that activation of additional signaling pathways is required, and these pathways may synergize with activated Wnt/β-catenin cascade to promote HB development . In a recent study from our group, we found that Yes-associated protein (YAP), the transcriptional co-activator downstream of the Hippo tumor suppressor pathway, is activated in most human HB samples, with coordinated activation of YAP and β-catenin being detected in ∼80% of HB . Importantly, co-expression of activated YAP and β-catenin in the mouse liver via hydrodynamic transfection led to HB formation in mice . Our study, therefore, establishes YAP as a second signal that synergizes with β-catenin to promote HB development. However, the molecular mechanisms whereby YAP promotes HB formation remain unknown.