YAP1 Signaling in Hepatobiliary Development and Oncogenesis

Yes-associated protein 1 (YAP1) is critical for liver development, regeneration, and oncogenesis. In this thesis, I studied the physiological role of YAP1 in early liver development, specifically in hepatoblasts as they developed into the major liver cell types, hepatocytes and cholangiocytes. I found that YAP1 was dispensable for hepatocyte differentiation from hepatoblasts but was essential for bile duct differentiation in mice, resulting in a phenotype like Alagille syndrome. There was complete loss of intrahepatic biliary network when Yap1 was conditionally deleted from hepatoblasts. Despite this, these mice survived long-term through genetic reprogramming of hepatocytes, favoring proliferation at the expense of metabolic function including bile acid metabolism, and reversing bile acid transport to promote excretion via the kidneys. Also, these mice did not exhibit any hepatocyte-derived biliary regeneration, in contrast to other models of bile duct paucity, showing that YAP1 is critical for hepatocyte transdifferentiation into cholangiocytes. I also developed a novel tissue clearing method for liver, which combined with ribbon-scanning confocal microscopy can be used for 3D imaging of intact tissue structures and can be adapted to understand tissue architecture of many liver pathologies. I also studied the role of YAP1 in hepatoblastoma (HB), a pediatric tumor which arises from hepatoblasts during development, with Dr. Danielle Bell and Dr. Hong Yang. Concomitant YAP1 and b-catenin activation causes HB tumor formation in mice. Using this model, we identified that Lipocalin 2 is regulated synergistically by both YAP1 and b-catenin and can potentially be used a serum biomarker of tumor growth. Next, based on several studies suggesting that both YAP1 and b-catenin activate mTORC1 signaling to promote tumor growth, we tested the effect of rapamycin in our HB model. We show that mTORC1 inhibition delays tumor formation and results in slower-growing tumors with more well-differentiated HB tumor cells, which tend to be less aggressive and more responsive to chemotherapy. Altogether, this thesis presents new insights into the distinct roles of YAP1 in biliary development and hepatoblastoma tumorigenesis and sets the stage for further mechanistic study to identify how YAP1 exerts such profound effects on liver formation