Abstract
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.
Footnotes
↵* These authors co-supervised the work.
List of Abbreviations: HCC, hepatocellular carcinoma; AAV, Adeno-Associated viral; TAM, Tamoxifen; mHCCs, mouse hepatocellular carcinomas; 4-OHT, 4-hydroxytamoxifen; DEG, differentially expressed genes; GSEA, Gene Set Enrichment Analysis; wt, wild-type; Doxy, Doxycyline; TCGA, The Cancer Genome Atlas; NES, Normalized Enrichment score; FDR, False Discovery Rate.
Financial Support: This study was supported by funding from the European Research Council (grant agreement no. 268671-MYCNEXT), the Italian Health Ministry (RF-2011-02346976) and the Italian Association for Cancer Research (AIRC, IG 2012-13182 and 2015-16768) to B.A., from Worldwide Cancer Research (15-1260) to A.S. and from AIRC to S.C. (IG 2018-21663).