Abstract
Metabolic rewiring of cancer stem cells plays a pivotal role in promoting tumorigenicity and recurrence in glioblastoma (GBM), making tumor recurrence inevitable. The presence of glioblastoma stem cells (GSCs) is a major factor behind the poor prognosis of GBM. Despite trimodal therapy, surgical resection, temozolomide chemotherapy, and radiotherapy, GSCs often invade into eloquent brain areas, become unresectable and resistant to treatment, promoting recurrence. GSCs leverage the postoperative wound healing period to invade into critical brain regions, making therapeutics less effective due to the inability to seek and destroy these GSCs. The recurrent nature of GBM negatively impacts conventional treatment strategies leading to a growing need for alternate therapeutic strategies. In this dissertation, we demonstrate a linear relationship between metabolic substrate utilization, stemness, and tumorigenicity in GBM. Transcriptomic analyses of patient derived GSCs and using known inhibitors of metabolic substrate utilization indicated that fat utilization fuels stemness and tumorigenicity of GSCs. We identified a distinct stemness-driven genomic difference between recurrent and newly diagnosed tumors, emphasizing the role of metabolism in fueling recurrence. Through metabolic studies in the patient derived GSCs, we were able to establish that the GSCs majorly rely on utilizing fatty acids by performing fatty acid oxidation (FAO), while depending less on glucose or glutamine oxidation for their energy requirements. We were able to determine that inhibiting the preferred metabolic substrate utilization, i.e., FAO, in GSCs by knocking out CPT1A contributes to a remarkable change in stemness potential and a significant reduction in the tumorigenic potential of the GSCs. we study the effect of a non-invasive and non-pharmacological intervention by utilizing a low carbohydrate high fat diet (LCHFD) in delaying and/or stopping proliferation of GSCs, with an aim to leverage this understanding to answer the clinically unmet needs.