Background & Aims: Activation of MYC and CTNNB1 (encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. Approach & Results: We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or Apc loss) upon expression of CRE recombinase in the liver, and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles and tumorigenesis. Conditional activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the mouse liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes followed by RNA-seq profiling allowed the identification of a "Myc/β-catenin signature", composed of a discrete set of Myc-activated genes whose expression increased in presence of active β-catenin. Notably this signature enriched for targets of Yap and Taz, two transcriptional co-activators known to be activated by WNT/β-catenin signaling, and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis. Conclusions: Yap and Taz mediate the cooperative action of Myc and β-catenin in liver tumorigenesis. This warrants efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β-catenin activity.

Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/Taz