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Title: Trafficking and signalling of oncogenic met
Author: Joffre, Carine
ISNI:       0000 0004 2684 5933
Awarding Body: Institute of Cancer Research (University Of London)
Current Institution: Institute of Cancer Research
Date of Award: 2010
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The Receptor Tyrosine Kinase (RTK) Met influences behaviour of several cancers by controlling growth, survival and metastasis. Recently, compartmentalisation of signals generated by RTKs, due to their endocytosis / trafficking, has emerged as a major determinant of various cell functions. The aim of my project was to study oncogenic Met signalling in relation to endosomal trafficking and to determine the consequences of such spatial changes on tumour cell growth and migration in vitro and in vivo. The model studied was NIH3T3 cells stably transfected with Wild type (Wt) Met or with three distinct mutants reported in human cancers. I found that two activating mutations in the kinase domain are highly tumorigenic in vivo. Using functional assays and tumour growth experiments, I demonstrated that one mutant is highly sensitive to Met specific tyrosine kinase inhibitors (TKI) while another is resistant. Such results suggested that therapeutical approaches to these mutants should be different. Furthermore, I demonstrated a direct link between endocytosis and tumorigenicity, suggesting a major role for Met endosomal signalling in cancer progression. Using confocal microscopy and quantitative biochemical assays, I demonstrated that Met mutants displayed an increased endocytosis and recycling and a decreased degradation profile. This led to an accumulation of phosphorylated Met on endosomes that induced activation of the GTPase Rac1, loss of stress fibres and increased cell migration. Blocking endocytosis by pharmacological and genetic 4 means inhibited mutants’ anchorage independent growth and, strikingly, tumorigenesis and experimental metastasis. Interestingly, the mutant resistant to TKI inhibition was sensitive to endocytosis inhibition. Taken together, these results suggest that Met localisation constitutes a major determinant in neoplastic development, while Met activation alone is insufficient to effect this change.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine