Role of the EMT activator ZEB1 in pancreatic cancer invasion, dissemination and metastasis

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Metastasis is the main cause of cancer associated death. We proposed that metastasis is triggered by an epithelial-mesenchymal transition (EMT), enabling dissemination and a subsequent epithelial re-differentiation (MET), enabling metastatic colonization. This concept of tumor cell plasticity is now experimentally validated and further extended to the cancer stem cell concept, by showing that EMT not only confers cancer cell motility but also maintains stem cell properties. We showed that the EMT-activator ZEB1 triggers cancer cell plasticity and tumor progression in cell culture or xenograft models. We now use a conditional Zeb1 knockout mouse to investigate the effects of Zeb1-depletion in a genetic mouse model for pancreatic cancer. Our preliminary results show that Zeb1 knockout tumors as well as derived cell lines are fixed in a differentiated, epithelial state and exhibit reduced metastasis. In the proposed project, we plan to uncover in detail how Zeb1 is stimulating metastasis and tumor cell plasticity in this mouse model. We also want to expand our analyses on the role of Zeb1 in the formation and function of circulating and disseminating tumor cells as well in the development of drug resistance. Understanding these molecular links will be the basis for developing new therapeutic strategies to prevent and fight metastasis.