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Title: Metabolic rewiring in response to genetic and environmental preturbations in cancer
Author: Hollinshead, Katy Elizabeth Rose
ISNI:       0000 0004 5994 3820
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2016
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Cancer cells reprogram their metabolism to supply biosynthetic and bioenergetic demands of rapid proliferation. Microenvironmental changes, such as hypoxia, further influence tumour metabolism, driving malignancy. Recent identification of cancer-associated mutations in succinate dehydrogenase (SDH), fumarate hydratase and isocitrate dehydrogenase (IDH) have shown that genetic alterations can directly alter tumour cell metabolism, and may be required for malignant transformation. Mutations in these metabolic enzymes promote tumorigenesis by hijacking the adaptive response to hypoxia. Understanding the metabolic vulnerabilities associated with these mutations may therefore elicit the design of more selective therapies. Employing a combination of analytical approaches to study metabolism, the research objectives were to characterise metabolic vulnerabilities associated with cells mutated in SDHB and IDH1. Results show that cells deficient in SDH activity maintain proliferation and viability by increasing dependency on pyruvate carboxylase for de novo aspartate synthesis. Mutations in IDH1 have a complex role in the metabolic adaptation to hypoxia, partially compromising this hypoxic response, yet also demonstrating aspects of pseudohypoxia, such as increased proline anabolism. This thesis reveals a metabolic vulnerability that could be therapeutically targeted to treat SDH-mutated tumours, and a novel redox-sensitive metabolic pathway, exhibited by both pseudohypoxic SDH and IDH1 mutated tumours, used to retain metabolic plasticity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology ; QH426 Genetics ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)