Citations 2
TMET-54. Rewiring of cortical glucose metabolism fuels human brain cancer growth
O’Brien, Alexandra, Bailleul, Justine , Zhou, Weihua , Xu, Jie , Lin, Angelica , Wilder-Romans, Kari , Korimerla, Navyateja , Feng, Jiane, Zhang, Li , Andren, Anthony , Tarnal, Vijay , Redic, Kimberly, Qi, Nathan , Fischer, J, Suresh, Krithika , Venneti, Sriram , Vlashi, Erina , Wahl, Daniel , Scott, Andrew J. , Mittal, Anjali , Meghdadi, Baharan , Palavalasa, Sravya , Achreja, Abhinav , Liang, Ningning , Kothari, Ayesha U. , Edwards, Donna , Wu, Zhe , Sajjakulnukit, Peter , Park, Junyoung O. , Hoeve, Johanna ten , Fischer, Joshua, Yang, Ethan , Regan, Michael S. , Stopka, Sylwia A. , Baquer, Gerard , Sarkaria, Jann N. , Lawrence, Theodore S. , Agar, Nathalie Y.R. , Lyssiotis, Costas A. , Al‐Holou, Wajd N. , Nagrath, Deepak
Neuro-Oncology | November 11, 2025 | Volume: 27 | Issue: Supplement_5 | Pages: v440-v441
Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to drive aggressive growth remains elusive. Here, we infused 13C-labeled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumor vs. cortex. Through the first direct and comprehensive measurements of carbon and nitrogen labeling in both cortex and glioma tissues, we uncover profound metabolic transformations. In human cortex, glucose carbons fuel essential physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters GBM metabolism, slows tumor growth, and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumors exploit glucose to suppress normal physiological activity in favor of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.
GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress
Zhou, Weihua , Zhao, Zitong , Lin, Angelica , Yang, John Z. , Xu, Jie , Wilder-Romans, Kari , Yang, Annabel , Li, Jing , Solanki, Sumeet , Speth, Jennifer M. , Scott, Andrew J. , Wang, L. , Wen, Bo , Andren, Anthony , Zhang, Li , Yao, Yangyang , Peterson, Erik , Korimerla, Navyateja , Werner, Christian K. , Ullrich, Alexander , Liang, Jessica , Jacobson, Janna , O’Brien, Alexandra M., Elaimy, Ameer L. , Ferris, Sean P. , Zhao, Shuang G. , Zhang, Shuqun , Al‐Holou, Wajd N. , Umemura, Yoshie , Morgan, Meredith A. , Lawrence, Theodore S. , Lyssiotis, Costas A. , Peters‐Golden, Marc , Wahl, Daniel , Walker, Natalie , Scott, Andrew J , Wang, Lu , Wen, Bo , Andren, Anthony , Zhang, Li , Kothari, Ayesha U , Yao, Yangyang , Peterson, Erik , Korimerla, Navyateja , Werner, Christian K , Ullrich, Alexander , Liang, Jessica , Jacobson, Janna , Palavalasa, Sravya , O'Brien, Alexandra M , Elaimy, Ameer L , Ferris, Sean P , Zhao, Shuang G , Sarkaria, Jann N , Győrffy, Balázs , Zhang, Shuqun , Al-Holou, Wajd N , Umemura, Yoshie , Morgan, Meredith A , Lawrence, Theodore S , Lyssiotis, Costas A , Peters-Golden, Marc , Shah, Yatrik M , Wahl, Daniel , Kothari, Ayesha U. , Sarkaria, Jann N. , Győrffy, Balázs
Cancer Discovery | October 30, 2023 | Volume: 14 | Issue: 1 | Pages: 158-175
ABSTRACT How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes nonhomologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard-of-care genotoxic treatments. The GTP–Rac1–PP5–Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in nonmalignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment. SIGNIFICANCE: A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues. This article is featured in Selected Articles from This Issue, p. 5