Abstract 2305: Identifying inhibitors of Epithelial-mesenchymal transition to prevent metastasis using global gene expression profile and a systems biology tool

Abstract

Abstract Acquisition of mesenchymal phenotype by epithelial cells by a process known as “Epithelial mesenchymal transition (EMT)” is considered an initiating event in the process of tumor metastasis. EMT confers certain fundamental abilities to cancer cells that are essential for metastasis which includes the ability to invade, induce immunosuppression, resistance to anoikis and therapeutic agents. The gene expression signature of EMT was shown to correlate with poor differentiation of tumors and patient survival. In addition, EMT was implicated in conferring stem cell like properties to resulting mesenchymal cells, highlighting the relevance of this process in metastasis. Therefore, inhibition of EMT is a rational therapeutic strategy to prevent metastasis. Among the cytokines rich in tumor microenvironment Transforming growth factor (TGF)-β is a potent inducer of EMT. Utilizing the global gene expression profile following TGF-β-induced EMT in A549 lung adenocarcinoma cell line, here we demonstrate a systems biology approach for identifying potential EMT inhibitors. In this approach, a publicly available data base (www.broad.mit.edu/cmap) comprising of gene expression profiles obtained from four different cell lines in response to 164 compounds which include both FDA approved drugs and non-drug bioactive agents, was used to derive negative correlations to EMT gene expression profile using Connectivity map, a pattern matching tool. This analysis identified a list of compounds with significant negative C-scores which may serve as potential EMT inhibitors. The molecules with the highly significant negative C-scores include inhibitors of PI3K (LY294002, Wortmanin), mTOR (Tacrolimus, Sirolimus), HSP90 (Geldanamycin) and COX1/2 (Indomethacin, Aspirin), and a PPAR-γ agonist Troglitazone. With the exception of PI3K inhibitors, the other molecules are potential new EMT inhibitors. PI3K inhibitors were previously demonstrated to inhibit EMT in breast epithelial cells. So far, we validated the ability of Troglitazone, PI3K and mTOR inhibitors to block TGF-β-induced EMT in A549 cells and in all cases we demonstrated that these molecules can selectively block acquisition of mesenchymal phenotype but have no effect on the loss of epithelial phenotype during EMT. Consistently, these molecules also inhibited EMT-induced migration and invasion of A549 cells. Validations of other molecules with significant C-scores are in progress. Above data demonstrates that connectivity maps based systems approach is a viable strategy and identifies inhibitors of PI3K and mTOR and agonists of PPAR-γ as potential therapeutic agents for prevention of metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2305.