Abstract IA26: Regulation of epithelial versus mesenchymal polarity and malignant progression

Abstract The ability of carcinoma cells to acquire cell-biological phenotypes associated with advanced malignancies is increasingly associated with activation of the EMT (epithelial-mesenchymal transition) program. Among the acquired phenotypes are those of motility, invasiveness, the ability to disseminate, and the ability to form increased numbers of tumor-initiating cells/cancer stem cells (CSCs). We have investigated the regulation of the EMT program and found that a key intracellular determinant is the levels of the cAMP second messenger molecule. When elevated, it causes exit of more mesenchymal carcinoma cells into an epithelial state. The formation of the CSCs within tumors has long been posited to arise following the conversion of normal tissue SCs into CSCs. However, in our hands, in a transgenic model of breast carcinoma formation, the SCs reside in one cell layer of the mammary ducts while the CSCs arise in another, making the direct derivation of CSCs from normal SCs unlikely, at least in this experimental model of mammary carcinogenesis. Once the EMT program is activated, carcinoma cells are able to acquire attributes that not only enable their dissemination from the primary tumor but also affect their subsequent post-extravasation proliferation in the lung parenchyma. The basis of this proliferation derives from the EMT-induced ability of extravasated carcinoma cells to form mature focal adhesions and activate the mitogenic signaling pathway via focal adhesion kinase (FAK). Additional consequences of EMT action will be discussed. Citation Format: Diwakar Pattabiraman, Diwakar Pattabiraman, Tsukasa Shibue, Tsukasa Shibue, Xin Ye, Xin Ye, Robert A. Weinberg, Robert A. Weinberg, Robert A. Weinberg. Regulation of epithelial versus mesenchymal polarity and malignant progression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA26.