Surgery (St Vincent's) - Theses
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ItemRole of Epithelial Mesenchymal Plasticity associated cancer subpopulations in mammary tumourigenisis and chemoresistance( 2014)Tumour heterogeneity is a key characteristic of cancer and has significant implications relating to tumour response to chemotherapy as well as patient prognosis and potential relapse. It is increasingly accepted that tumours are clonal in origin, suggestive of a tumour arising from a deregulated or mutated cell. Cancer stem cells (CSC) possess/propagate these capabilities, and with appropriate intracellular triggers and/or signalling from extracellular environments, can ‘differentiate’ to initiate tumour formation. Additionally through epithelial mesenchymal plasticity (EMP), where cells gain and maintain characteristics of both epithelial and mesenchymal cell types, epithelial-derived tumour cells have been shown to ‘de-differentiate’ to acquire cancer stem attributes, which also imparts chemotherapy resistance. This new paradigm places EMP centrally in the process of tumour formation, propagation, progression and metastasis, as well as modulating drug response to current forms of chemotherapy. Furthermore, EMP and CSCs have been identified in cancers arising from different tissue types making them a possible generic therapeutic target in cancer biology. In this study, we expand on the relationship between tumour heterogeneity, EMP and CSC in BrCa through the identification and characterisation of epithelial and mesenchymal subpopulations within two BrCa cell lines. In addition, we demonstrate the plasticity that allows these cell populations to effectively regenerate the other cell populations with a particular emphasis on the CSC phenotype. Through a functional genomics screen, the importance of the mesenchymal phenotype in tumour initiation is demonstrated. Taken together, this study demonstrates that heterogeneity exists at a cell line level and this heterogeneity differs in different cellular systems. We also find evidence to suggest that BrCa cell lines can use multiple mechanisms to achieve an outcome such as tumour initiation or mammosphere formation, and subsequently emphasize the importance of phenotype specific drugs. This ideology of drug repurposing to identify phenotype specific drugs is explored through the use of the connectivity map database to identify new uses for previously established drugs to target these subpopulations find preliminary evidence for the role of HDACi to affect these EMP associated subpopulations in BrCa cell lines.