Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713119
Title: A metabolomic investigation of Rho-ROCK signalling in metastatic melanoma
Author: Kanno, Tokuwa
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Abstract:
Metastatic spread is the cause of 90% of cancer-related deaths. Melanoma cells with high actomyosin contractility, driven by high Rho-Rho Kinase (ROCK) signalling, exhibit a rounded amoeboid type movement and are found at the invasive fronts of primary tumours and in metastases. ROCK is a novel therapeutic target of melanoma as it has recently been shown that small molecule inhibitors of ROCK can reduce melanoma growth and the number of metastases in vivo. -Omics level studies of biological systems are quickly becoming an integral and routine part of biological research. Nuclear Magnetic Resonance (NMR) Metabolomics is a relatively cheap and highly reproducible means of identifying 30-100 different metabolites in a biological system. To date there has not been an -omic level study of ROCK regulation of cancer cell metabolism and this thesis addresses this gap in knowledge. In this thesis, we investigate how ROCK controls proliferation and promotes the rounded morphology. Applying NMR metabolomics to murine melanomas and human A375M2 melanoma cells we identify a substantial shift from glutamine metabolism to anaerobic respiration as the main effect of ROCK inhibition/silencing/knockout with substantial reductions in intracellular glutamate and myo-inositol and increases in saturated lipids and the methyl groups of lipids also detected. Further, analysis of glucose or glutamine-glutamate metabolism gene expression in melanoma patients reveals a greater dependence on the Warburg effect in primary tumours. Glutamine utilisation, correlated with ROCK, increases during metastasis. In the final section of this work, we show that ROCK1/2 silenced morphological, proliferative and metabolomic phenotypes in A375M2 cells are reproduced by silencing selected glutamate and/or glutamine transporters and, respectively, inhibition and silencing of AMPA and kainate receptors. It is possible that autocrine ionotropic glutamate receptor mediated signalling underpins ROCK dependent control of proliferation and actomyosin contractility in metastatic melanoma.
Supervisor: Mason, Andrew James ; Sanz Moreno, Victoria Marta Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.713119  DOI: Not available
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