Interaction of the EMT-activator ZEB1 and the Yap/Taz/Hippo-pathway in cancer

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Many solid cancers can be successfully removed by surgical resection. However two main clinical problems impede a cure or a long time survival of cancer patients: Metastasis and/or resistance to radio-/chemotherapy. The only option to improve the patients situation is the development of novel therapeutic strategies fighting such fatal processes and the basis for that is to uncover the underlying molecular mechanisms. Two cellular programmes/pathways - the epithelial-mesenchymal transition (EMT) and the Hippo-pathway - turned out to play crucial roles. In the proposed project, we aim to determine a direct functional interaction of these two oncogenic programmes/pathways, which exert similar effects in cancer cells. We have shown that the central EMT-activator ZEB1, similar to YAP, the major downstream effector of the oncogenic Hippo-pathway, is a major oncogenic factor by inducing the metastatic cascade and imposing a stemness- and drug resistance phenotype in cancer cells. Our preliminary data indicate that ZEB1 directly interacts with YAP, thus linking both oncogenic pathways. We now want to characterize the direct and functional interaction, determine its underlying molecular mechanisms and consequences as well as to validate its translational and clinical potential. The results will be the basis for novel therapeutic intervention strategies to interfere with malignant tumor progression and therapy resistance.