CBIO-09ENHANCED MITOCHONDRIAL RESPIRATION IN SLOW-CYCLING GLIOMA STEM CELLS

Abstract

INTRODUCTION: Tumorigenesis and resistance to treatment result from the ability of specific subpopulations of tumor cells to expand and survive. Conventional therapies effectively eliminate rapidly dividing cells, which derive their energy from aerobic glycolysis, but spare slowly dividing populations. We previously reported the existence of slow-cycling cells that exhibit cancer stem cell (CSC) characteristics and resistance to therapies in glioblastoma (GB). Clinical strategies targeting this specific phenotype could lead to improved therapeutic outcomes and reduce disease progression or recurrence. OBJECTIVES: Metabolic reprogramming is now a well- recognized hallmark of cancers and represents a promising therapeutic target. The primary objective of this study was to characterize the energetic properties of CSCs, especially slow-cycling cells. METHODS: Slow and fast-cycling cells were isolated from patient-derived primary GB cells via a dye retention assay using carboxy fluorescein succinimidyl ester. RESULTS: Mass spectrometry-based metabolite screening revealed metabolic heterogeneity with differential metabolic signatures between GB fast and slow-cycling cells. An OxPhos profile was validated in the slow-cycling cells by the observation of greater mitochondrial activity as well as upregulation of key proteins involved in the Krebs cycle and mitochondrial electron transport chain, such as pyruvate dehydrogenase, NADH dehydrogenase, and ATP synthase. Conversely, glycolytic proteins such as lactate dehydrogenase A were upregulated in fast-cycling cells. We also found that the slow-cycling fraction was less sensitive to glucose restriction than the fast-cycling portion, as shown by increased survival in glucose-deprived conditions, suggesting ability to metabolize diverse energy sources. CONCLUSION: These studies demonstrate metabolic diversity in GB and suggest that GB slow-cycling cells, exhibiting catabolic adaptability, utilize OxPhos to meet energy demands. This represents an unexpected selective vulnerability in GB cells that could be targeted for therapy.