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Title: c-MET as a key regulator of an invasive and migratory phenotype in colorectal cancer
Author: Bradley , Conor Aidan
ISNI:       0000 0004 5994 9173
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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In the current study, we initially investigated the molecular mechanisms driving tumour cell migration and invasion in vitro using in-house generated invasive CRC cell line models, with which we reported an association between HGF-independent overexpression and hyper-phosphorylation of c-MET with a mesenchymal, migratory and invasive phenotype. Upon identification of this association, we subsequently demonstrated that RNAi-mediated ablation of c-MET abolished the basal migratory and invasive potential of CRC cell lines, illustrating a key role for c- MET expression in regulation of these phenotypes. Using a molecular pathology based methodology incorporating RNAscope®, a novel quantitative mRNA in situ hybridisation technique, we translated our observations in vivo, whereby we demonstrated that the MET transcript is significantly upregulated in tumour budding foci at the invasive edge of stage III CRC tumours. Upon evaluation of the role of the TME in dictating tumour cell phenotype using an in vitro coculture methodology, we highlighted a role for colonic myofibroblasts in promoting a migratory and invasive phenotype, and minor resistance to MEK1/2 inhibition in KRASMT CRC cell lines. Importantly, subsequent molecular characterisation revealed HG F as a major fibroblast-derived factor that was promoting these phenotypes through phosphorylation of c-MET, whereby neutralisation of HGF could partially abolish the pro-invasive fibroblast-derived signal. Finally, in attempting to assess the role of c-MET as a prognostic biomarker in early stage CRC, we demonstrated an apparent disparity between the prognostic value of MET gene expression and cMET protein expression, whereby only the former could predict poor outcome. Collectively, our study provides pre-clinical rationale for further investigation of therapeutic inhibition of the HGF/cMET pathway in the adjuvant setting to circumvent metastasic dissemination and therefore halt recurrence.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available