Differential requirement of Hippo cascade during CTNNB1 or AXIN1 mutation‐driven hepatocarcinogenesis

Background and Aims: Gain‐of‐function (GOF) mutations of CTNNB1 and loss‐of‐function (LOF) mutations of AXIN1 are recurrent genetic alterations in hepatocellular carcinoma (HCC). We aim to investigate the functional contribution of Hippo/YAP/TAZ in GOF CTNNB1 or LOF AXIN1 mutant HCCs. Approach and Results: The requirement of YAP/TAZ in c‐Met/β‐Catenin and c‐Met/sgAxin1‐driven HCC was analyzed using conditional Yap , Taz , and Yap;Taz knockout (KO) mice. Mechanisms of AXIN1 in regulating YAP/TAZ were investigated using AXIN1 mutated HCC cells. Hepatocyte‐specific inducible TTR‐CreER T2 KO system was applied to evaluate the role of Yap;Taz during tumor progression. Cabozantinib and G007‐LK combinational treatment were tested in vitro and in vivo . Nuclear YAP/TAZ was strongly induced in c‐Met/sgAxin1 mouse HCC cells. Activation of Hippo via overexpression of Lats2 or concomitant deletion of Yap and Taz significantly inhibited c‐Met/sgAxin1 driven HCC development, whereas the same approaches had mild effects in c‐Met/β‐Catenin HCCs. YAP is the major Hippo effector in c‐Met/β‐Catenin HCCs, and both YAP and TAZ are required for c‐Met/sgAxin1‐dependent hepatocarcinogenesis. Mechanistically, AXIN1 binds to YAP/TAZ in human HCC cells and regulates YAP/TAZ stability. Genetic deletion of YAP/TAZ suppresses already formed c‐Met/sgAxin1 liver tumors, supporting the requirement of YAP/TAZ during tumor progression. Importantly, tankyrase inhibitor G007‐LK, which targets Hippo and Wnt pathways, synergizes with cabozantinib, a c‐MET inhibitor, leading to tumor regression in the c‐Met/sgAxin1 HCC model. Conclusions: Our studies demonstrate that YAP/TAZ are major signaling molecules downstream of LOF AXIN1 mutant HCCs, and targeting YAP/TAZ is an effective treatment against AXIN1 mutant human HCCs.