Identifying the metabolic 'Achilles heel' of adult and paediatric glioblastoma multiforme

Wood, James (2019) Identifying the metabolic 'Achilles heel' of adult and paediatric glioblastoma multiforme. PhD thesis, University of Nottingham.

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Abstract

Despite substantive efforts to characterise glioblastoma multiforme (GBM) at the molecular level, improvements to the overall survival of patients have yet to be seen within the clinic. Intratumour heterogeneity describes the co-existence of several subpopulations of GBM cells that are genetically distinct. This phenomenon provides one mechanism by which GBM recurs via the presence of resistant subclonal cells. However, questions remain as to whether cancer cell metabolism demonstrates the same level of heterogeneity given the metabolic regulatory role of several oncogenes and tumour suppressors. We applied liquid chromatography-mass spectrometry to profile the metabolome and lipidome of tumour fragments sampled from adult GBM patients. The extent of heterogeneity in metabolomic and lipidomics profiles differed between patients but was predominantly observed between non-invasive and invasive regions. Evidence for normal brain metabolism influencing the metabolomic profile of the invasive region was detected, calling for isolation of the tumour cell component. Despite this caveat, dysregulated proline metabolism was identified for further mechanistic and therapeutic study.

The identification of intratumour metabolic heterogeneity in GBM has therapeutic implications in terms of the utilisation of single-agent therapies targeting metabolism. However, elucidation of a metabolic dependency in GBM cells representing an ‘Achilles heel’ may circumvent intratumour genetic heterogeneity. Glucose is not the only nutrient utilised by cancer cells. The dependence of GBM cells on external sources of lipid and cholesterol species in the form of lipoproteins was assessed to determine the consequences on cellular viability and metabolism. Growth inhibitory responses were demonstrated under lipoprotein deficient conditions, associated with cell line-specific responses indicative of different metabolic stress responses in adult and paediatric GBM. Consistent observation of reduced cellular cholesterol levels across all cell lines presented a metabolic vulnerability that was pharmacologically replicated using liver X receptor (LXR) agonists. The identification of reduced cellular viability following exposure to LXR agonists and transcriptomic responses associated with a reduced proliferative response provide impetus for further drug development in terms of combination strategies and alleviation of deleterious side-effects.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Grundy, Richard
Rahman, Ruman
Keywords: Glioblastoma multiforme; Heterogeneity; Metabolomic profile; Metabolic vulnerability
Subjects: QS-QZ Preclinical sciences (NLM Classification) > QZ Pathology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 56086
Depositing User: Wood, James
Date Deposited: 19 Jul 2019 04:40
Last Modified: 19 Jul 2019 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/56086

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