TMET-19. REWIRING OF CORTICAL GLUCOSE METABOLISM FUELS HUMAN BRAIN CANCER GROWTH

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Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. In particular, we find that cortical tissue produces its own glucose-derived serine, whereas gliomas predominantly consume serine from the environment. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth. Combining dietary serine restriction with chemoradiation reduces brain tumor growth in mice, suggesting that such a dietary intervention could improve outcomes for patients with high grade glioma.

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