{'fraction_non_alphanumeric': 0.033598045204642636, 'fraction_numerical': 0.009773976786805132, 'mean_word_length': 5.658536585365853, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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.