The role of the epithelial-mesenchymal transition in aggressive tumour phenotypes
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The epithelial-mesenchymal transition (EMT) is an evolutionarily conserved developmental process characterized by the loss of intercellular contacts, changes in cell polarity and increased migration and invasion. EMT has recently been shown to have a significant impact on chemotherapy response and metastatic progression in cancer cells. We hypothesized that because EMT contributes to aggressive cancer phenotypes, expression profiles of key EMT modulators could be profiled in ovarian and prostate tumours to distinguish aggressive from non-aggressive disease. Our results demonstrated that increased EMT gene expression was correlated with chemotherapy resistance in ovarian cancer, and with higher Gleason pattern in prostate cancer, confirming an association between EMT and increased risk for cancer progression. This underscores the potential for EMT gene signatures to be used as clinically relevant predictive and prognostic biomarkers. Functional studies using in vitro models of Cisplatin-resistant ovarian cancer and invasive prostate cancer demonstrated that inhibition of EMT signaling, both through the dysregulation of key transcription factors (SNAI1, SNAI2, ZEB1), and repressed expression of phenotypically important genes such as VIM, SPARC, CLTC and HIF1A resulted in loss of aggressive attributes in these cell lines. This included re-sensitization of our ovarian cancer cells to the effects of Cisplatin, while significantly reducing cell migration and invasion in our prostate cancer cells, both in 2- and 3-dimensional culture models. Furthermore, using our prostate cancer knockdown cell lines, we were able to assess gene expression changes in response to single gene repression. As a result, those genes that appear to have the highest degree of connectivity within the context of our EMT network were identified, thus contributing to the overall understanding of EMT regulation. Ultimately, we have been able to assess the role of the epithelial-mesenchymal transition in aggressive tumour behaviours, such as resistance to chemotherapy and progression towards metastatic events. The results of this work indicate that gene expression signatures associated with EMT may be useful as predictive and prognostic biomarkers in various cancer types. Furthermore, gene knockdown studies have provided insight into EMT signaling network regulation, as well as the functional contribution of a number of genes to alterations in migratory and invasive cancer cell programs.