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Title: Modulation of cancer cell invasion by extracellular vesicles
Author: Tognoli, Maria Laura
ISNI:       0000 0004 7966 2735
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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The cancer microenvironment is a receptacle of stimuli necessary to promote tumour growth. The role of extracellular vesicles (EVs) in orchestrating a crosstalk between cancer cells and other cell types in the surroundings is integral part of the tumour network. Extracellular vesicles are subcellular structures that emanate virtually from any cell type and carry information both within the primary tumour site and to distant sites. Here I show that two oncogenic stimuli control the release of EVs to render cancer and untransformed cells more aggressive. Firstly, I show that loss of the tumour suppressor RASSF1A in breast cancer cells allows the alternative transcript and oncogene RASSF1C to exploit its tumourigenic activity through enhanced secretion of EVs. I characterise RASSF1C EVs as able to drive migration and invasion in recipient breast cancer cells and I show that RASSF1C elicits exocytosis through activation of the small GTPase RhoA. Secondly, I explore the role of the TGF β cytokine in altering extracellular vesicle secretion. Here, I report the selective enrichment of the tetraspanin CD9 on TGF β driven EVs. I show that CD9 is a positive mediator of TGF β pathway and conclude that TGF β employs exocytosis as a route to secrete CD9 from pathway activated cells, as a negative feedback on the signalling cascade. Finally, I describe a novel role of CD9 positive EVs in propagating TGF-β signalling in recipient breast cancer cells and in mediating TGF-β driven invasion in untransformed breast epithelium. This work highlights the importance of tumourigenic stimuli, both intracellular (RASSF1C) and environmental (TGF-β), in fostering a pro invasive cancer environment and the pivotal role that extracellular vesicles play in mediating oncogenic signalling.
Supervisor: O'Neill, Eric Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available