Intracytoplasmic lipid droplets in high grade glioma: metabolism and target for therapy

Murren, Robert John (2018). Intracytoplasmic lipid droplets in high grade glioma: metabolism and target for therapy. University of Birmingham. Ph.D.

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Abstract

Glioblastoma is a highly malignant and aggressive high grade glioma with a poor prognosis. The low survival rates stem from tumour progression, late intervention, ineffective therapies and drug resistance, requiring new therapeutic and diagnostic approaches. Lipid droplets are dynamic organelles suggested to be influential facets of cancer metabolism and biology in many tumours. In glioblastoma lipid droplets have been associated with hypoxia higher clinical grades and poor survival however the cellular pathways underlying lipid droplet metabolism remain unclear. Using a publically available database of grade 2 ta 4 glioma gene expression, we observed that genes associated with lipid droplet metabolism were important prognostic survival and tumour progression indicators. Moreover, through confocal microscopy, flow cytometry and NMR-based methods, we observed that uptake of exogenous lipids and adipose triglyceride lipase-mediated lipid shuttling produced lipid droplets whilst autophagy was vital to lipid droplet breakdown. ATGL-mediated lipid shuttling was further observed to prevent unsaturated fatty acid oxidative damage. Finally, we investigated the effect of pharmacological lipid droplet manipulation and observed that autophagy inhibition can improve temozolomide and irradiation cytotoxicity. Taken together our data suggests that understanding lipid droplet metabolic pathways may generate prognostic bio-markers of survival and progression and improve current therapies.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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