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Title: Heterogeneity in melanoma and the microenvironment
Author: Manning, C. S.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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This thesis addresses the signalling pathways and gene networks associated with melanoma cell motility in vivo and heterogeneity in tumour-associated vasculature. Melanoma metastasis begins with the acquisition of motility in the primary tumour, however, there is little characterisation of signalling pathways or microenvironments associated with melanoma motility in vivo. Intra-vital imaging of clonal signalling reporter cell-lines showed heterogeneous cell behaviour in vivo and increased Notch, TGF-β and SRF dependent transcription in motile cells. Further investigations into Notch signalling in melanoma metastasis showed that Notch promotes metastasis through cell-autonomous and non-cell autonomous mechanisms. The reporter cell-lines were used to enrich for the motile melanoma cell population and genes up-regulated in this population were identified. Many cell-cycle regulators, including regulators of cytokinesis, were up-regulated in the B16 F2 melanoma population enriched for motile cells. Bioinformatic analysis indicated that EZH2, a histone methyltransferase in the Polycomb repressor 2 complex, can regulate the genes associated with motile cells and EZH2 depletion decreased melanoma cell motility in vitro and metastasis in vivo. EZH2 was also shown to regulate cell morphology and the actin cytoskeleton through regulating activation of a subset of ERM proteins. Due to association between melanoma metastasis and differentiation, the role of EZH2 in melanoma differentiation state was investigated. EZH2 depletion did not significantly affect expression of melanoma differentiation markers but increased Oca2 mRNA expression leading to increased pigment. This thesis also investigates heterogeneity in the tumour microenvironment. Morphologically and dynamically distinct regions of the tumour vasculature were identified by intra-vital imaging and quantitative image analysis, and these regions could be followed over time using imaging windows. The tumour vasculature showed a heterogeneous response to the anti-angiogenic drug, Sunitinib, possibly due to microenvironmental factors. Aspects of vascular morphology and dynamics correlated with melanoma motility and may be used to describe microenvironments favourable for motility.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available