The role of the Hippo pathway in etiology and progression of pancreato-biliary tumors and clear cell renal cell carcinoma

In the quest for the discovery of novel targets for cancer therapy, aberrantly reactivated embryonic signaling pathways have proven to be a rich mine and recent years have seen the introduction of the hedgehog-inhibitor cyclopamine into clinical practice. Dysfunctional signaling via the growth inhibitory embryonic signaling pathway clustered around the Hippo kinase and aberrant expression of its main target Yes-associated protein (YAP) is likewise emerging to be involved in maintenance and progression of various human cancers. The purpose of this dissertation is to identify the incidence, functional relevance and mechanistic significance of aberrant Hippo signaling in etiology and progression of different solid tumor entities that vary in their biology as well as tissue of origin, but share an unfavorable clinical prognosis and the dire need for novel therapeutic approaches. Specifically cancers of the pancreato-biliary tract, more precisely pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCC), as well as clear cell renal cell carcinoma (ccRCC) have been analyzed in the course of this dissertation. For these tumor entities initial evidence of aberrant Hippo signaling has been published. In a first step, aberrant expression of the transcriptional co-activator YAP, which constitutes the principal target of the growth inhibitory Hippo-pathway, was confirmed in human tumor tissue samples by immunohistochemistry. Nuclear YAP expression correlated with nodal stadium in PDAC and was also more frequent in ccRCC patients with tumor-positive lymph nodes. A common feature in all three tumor entities were solitary, fibroblast-like cells residing inside the tumor adjacent stroma that were highlighted by robust nuclear YAP-staining, suggesting that YAP might be a mediator of tumor-stroma crosstalk. In a second step, the role of aberrant YAP activity in tumor cell lines was examined by shRNA-mediated knockdown of the protein in selected, highly YAP-expressing cell lines. Phenotypic consequences of the knockdown ...