Medicine (St Vincent's) - Theses

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    Epithelial - mesenchymal plasticity in circulating and disseminated tumour cells
    Metastasis, or the spread of cancer from the site of origin to a distant site, is the leading cause of cancer-associated death. The work presented in this thesis revolves around the process of metastasis in order to understand some of the underlying mechanisms. Specifically, the focus of this project was on cancer cells moving through the blood circulation, known as circulating tumour cells (CTC), as well as cancer cells that have escaped into a distant site but are undetectable by conventional screening methodologies, known as disseminated tumour cells (DTC). Collectively, CTC and DTC are often referred to as minimal residual disease. Whilst there is an exponentially growing amount of attention on minimal residual disease research, in addition to a large push towards the use of these cells (especially CTC) clinically, their clinical utility currently remains in limbo. The detection and enumeration of CTC/DTC in cancer patients has been demonstrated to associate with worse disease-free survival and overall survival, yet a relatively small proportion of cancer patients with detectable CTC/DTC do not fit the predicted relapse and/or survival trends. Thus, there is growing emphasis in published literature to delve beyond the simple detection of CTC/DTC, and into their characterization. The belief is that this will then enable one to identify a patient who bears CTC/DTC that are of actual biological concern. Particularly, the ability of cancer cells to switch between epithelial and mesenchymal states, or even display both epithelial and mesenchymal properties, has been proposed by our lab to be important in the generation and function of CTC/DTC. This ‘flexibility’ in cellular status has been termed in our lab as epithelial – mesenchymal plasticity (EMP). This project is divided into three main sections pertaining to; (i) establishment and optimisation of CTC/DTC capture and detection/analysis protocols, (ii) the use of xenograft mouse models for studying EMP in minimal residual disease, and (iii) the study of EMP in minimal residual disease of metastatic breast cancer patients. A number of other laboratories around the world also propose a role for EMP in CTC/DTC, and several publications have come forth in very recent years attempting to look into this phenomenon. However, to the best of our knowledge, (i) the work presented in this thesis is the first characterising the EMP status of CTC/DTC in Australia, and (ii) the only of its kind (globally) utilising the MDA-MB-468 and ED03 xenograft models to study minimal residual disease using our specific experimental design and ‘in-house’ developed assays.