E2f coordinates the proliferation and transdifferentiation of a Sox9+bile duct cell to initiate hepatocellular carcinoma

ABSTRACT Disruption of the Rb/E2f interaction is one of the six original hallmarks of cancer and is thought to confer unrestricted proliferative potential to tumor cells. Although E2f is active in almost all cancer cases as a result of this disruption, the consequence of its unrestricted activity for cancer initiation remains mostly unknown. To address this question, we genetically inactivated the entire Rb family of genes (Triple Knock Out, TKO) in specific cell lineages in the liver. Strikingly, this unbiased approach reveals that Rb family inactivation initiates a phenotypically similar hepatocellular carcinoma (HCC) from either periportal hepatocytes or Sox9+ bile duct cells. In the latter population, Rb family inactivation results in unrestricted proliferation as well as the E2f-driven transactivation of the pioneer factor Foxa3, which activates a “periportal hepatocyte-like” metabolic program to ensure transdifferentiation into hepatocytes. Notably, single or compound inactivation of E2f1 and E2f3 in the TKO background is sufficient to suppress Foxa3 expression and HCC initiation, without altering the proliferative status of Sox9+ bile duct cells. Collectively, our results reveal that derepression of a cell cycle gene program and activation of non-cell cycle oncogenic features by E2f are distinct consequences of disrupting the Rb/E2f interaction, and that coordinated activation of these two functions are essential for HCC initiation from a founder liver bile duct cell lineage. Competing Interest Statement The authors have declared no competing interest.