Chemoresistance as a consequence of Wnt-associated epithelial-mesenchymal transition

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During tumor progression, carcinoma cells frequently lose their epithelial and adopt a mesenchymal phenotype. This epithelial-mesenchymal transition (EMT) involves the activation of Wnt signaling pathways. Little is known about how EMT affects the response of tumor cells to chemotherapy. A system of human mammary epithelial cells, allows the isolation of a mesenchymal subset from a generally epithelial cell population (R. A. Weinberg lab). There, EMT is associated with and requires strongly enhanced canonical Wnt signaling activity. We found that EMT renders the cells resistant towards treatment with cisplatin, and also towards ultraviolet (UV) irradiation. The difference was reflected by differential accumulation of damaged DNA and phospho-histone 2AX (gammaH2AX). Histone deacetylase inhibitors reversed this resistance phenotype.We will now attempt to answer the following questions: What mechanisms reduce the accumulation of cisplatin-induced DNA damage in response to EMT, in mammary epithelial cells and cancers derived thereof? And could EMT-induced chemoresistance be overcome by antagonizing Wnt activity and/or chromatin remodeling? We will employ modulators of Wnt signaling and assess their chemosensitizing effects. This work is anticipated to clarify the mechanisms of chemoresistance conferred by EMT, and it will hopefully outline strategies to re-sensitize chemoresistant cancer cells.