Project Summary
During tumor progression, carcinoma-derived cells frequently adopt the properties of mesenchymal cells, including increased motility and invasion. This epithelial-mesenchymal transition (EMT) is frequently de-pendent on canonical and non-canonical Wnt signaling. Little is known at present how EMT affects the response of tumor cells to chemotherapy and irradiation.
Recently, a system of human mammary epithelial cells was established in a collaborating laboratory, al-lowing the isolation of a mesenchymal subset from a generally epithelial cell population. In this system, EMT correlates with strongly enhanced canonical Wnt signaling activity and the expression of beta-catenin-responsive target genes. Strikingly, we found that EMT renders the cells resistant towards cis-platin treatment and also towards ultraviolet (UV) irradiation, whereas the sensitivities towards other chemotherapeutics were differing less profoundly or not at all. The difference in sensitivity towards cis-platin and UV irradiation was not only observed with regard to apoptosis, but also through differential ac-cumulation of phospho-histone 2AX (gammaH2AX), and even when quantifying the DNA adducts directly formed by cisplatin or ultraviolet irradiation. Histone deacetylase inhibitors reversed this resistance pheno-type, arguing that EMT-associated chromatin remodeling forms the basis of differential chemosensitivity.
We will now attempt to answer the following questions: What mechanisms reduce the accumulation of cisplatin-induced DNA damage in response to Wnt activity and EMT? And how could EMT-induced chemoresistance be overcome? We will employ modulators of Wnt signaling and assess their chemosen-sitizing effects, alone or in combination with TGFbeta signaling intermediates and chromatin modifiers. This work is anticipated to reveal the mechanisms of chemoresistance conferred by EMT, and it will hope-fully outline strategies to re-sensitize cancer cells.