The Hippo Pathway in Liver Cancer Heterogeneity

The Hippo pathway is a conserved growth control pathway and it is being heralded as a promising target for cancer therapy. This is because hyperactivation of the Hippo pathway effectors Yes Associated Protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ) are sufficient to drive cell proliferation and malignancy of tumor cells, and because YAP and TAZ are commonly hyperactivated, not mutated, in a broad range of different human carcinomas (Johnson and Halder 2014). Indeed, YAP and TAZ are required for cancer cell development although the specific function of YAP/TAZ in cancer cells is not known. Surprisingly, our recent data show that YAP/TAZ are dispensable for homeostasis of adult 'healthy' organs in the mouse: knock out of YAP/TAZ in the liver and in blood vessels using the hepatocyte and endothelial specific inducible Cre recombinase system (VEcadherin-CRE and AAV8-TBG-CRE, respectively) results in no overt phenotypes and all animals were alive even after 10 months, the time point when tissues were harvested. This suggests that targeting the activity of YAP/TAZ may specifically affect cancer cells, and not normal tissues. In my thesis work I will test whether systemic inhibition of YAP and TAZ indeed specifically affects tumor cells and not normal peritumoral cells and other tissues. I will work with several different cancer models in the liver, namely b-Catenin-P53 driven hepatocellular carcinoma and Notch-Akt driven intrahepatic cholangiocarinoma. I chose these models for two main reasons. First YAP/TAZ are highly expressed in both tumor models. Second, although the incidence of both types of cancer is rising, the outcome is still very poor and better therapeutic approaches are urgently needed. I will use several different assays for tumor cells and other tissue: histology, in situ assays for cell proliferation, cell death, and cell differentiation; and transcriptional profiling to measure effects of loss of YAP and TAZ. My projects will thus unravel functions of the Hippo pathway effectors YAP and TAZ in cancer cells and how these differ from their functions in normal cells. Altogether these experiments will reveal cancer cell specific functions of YAP/TAZ and evaluate in vivo their value as anticancer targets.