Identifying Inhibitors of Epithelial-Mesenchymal Transition by Connectivity Map–Based Systems Approach

Background: Acquisition of mesenchymal phenotype by epithelial cells by means of epithelial-mesenchymal transition (EMT) is considered as an early event in the multistep process of tumor metastasis. Therefore, inhibition of EMT might be a rational strategy to prevent metastasis. Methods: Using the global gene expression profile from a cell culture model of transforming growth factor-&bgr; (TGF-&bgr;)-induced EMT, we identified potential EMT inhibitors. We used a publicly available database (www.broad.mit.edu/cmap) comprising gene expression profiles obtained from multiple different cell lines in response to various drugs to derive negative correlations to EMT gene expression profile using Connectivity Map, a pattern matching tool. Results: Experimental validation of the identified compounds showed rapamycin as a novel inhibitor of TGF-&bgr; signaling along with 17-AAG, a known modulator of TGF-&bgr; pathway. Both of these compounds completely blocked EMT and the associated migratory and invasive phenotype. The other identified compound, LY294002, demonstrated a selective inhibition of mesenchymal markers, cell migration and invasion, without affecting the loss of E-cadherin expression or Smad phosphorylation. Conclusions: Our data reveal that rapamycin is a novel modulator of TGF-&bgr; signaling, and along with 17-AAG and LY294002, could be used as therapeutic agent for inhibiting EMT. This study demonstrates the potential of a systems approach in identifying novel modulators of a complex biological process.

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