Rewiring of cortical glucose metabolism fuels human brain cancer growth

Scott, Andrew J.; Mittal, Anjali; Meghdadi, Baharan; O’Brien, Alexandra; Bailleul, Justine; Sravya, Palavalasa; Achreja, Abhinav; Zhou, Weihua; Xu, Jie; Lin, Angelica; Wilder-Romans, Kari; Liang, Ningning; Kothari, Ayesha U.; Korimerla, Navyateja; Edwards, Donna M.; Wu, Zhe; Feng, Jiane; Su, Sophia; Zhang, Li; Sajjakulnukit, Peter; Andren, Anthony C.; Park, Junyoung O.; Hoeve, Johanna; Tarnal, Vijay; Redic, Kimberly A.; Qi, Nathan R.; Fischer, Joshua L.; Yang, Ethan; Regan, Michael S.; Stopka, Sylwia A.; Baquer, Gerard; Suresh, Krithika; Sarkaria, Jann N.; Lawrence, Theodore S.; Venneti, Sriram; Agar, Nathalie Y. R.; Vlashi, Erina; Lyssiotis, Costas A.; Al-Holou, Wajd N.; Nagrath, Deepak; Wahl, Daniel R.

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Andrew J. Scott, Anjali Mittal, Baharan Meghdadi, Alexandra O’Brien, Justine Bailleul, Palavalasa Sravya, Abhinav Achreja, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Ningning Liang, Ayesha U. Kothari, Navyateja Korimerla, Donna M. Edwards, Zhe Wu, Jiane Feng, Sophia Su, Li Zhang, Peter Sajjakulnukit, Anthony C. Andren, Junyoung O. Park, Johanna Hoeve, Vijay Tarnal, Kimberly A. Redic, Nathan R. Qi, Joshua L. Fischer, Ethan Yang, Michael S. Regan, Sylwia A. Stopka, Gerard Baquer, Krithika Suresh, Jann N. Sarkaria, Theodore S. Lawrence, Sriram Venneti, Nathalie Y. R. Agar, Erina Vlashi, Costas A. Lyssiotis (), Wajd N. Al-Holou (), Deepak Nagrath () and Daniel R. Wahl ()
Additional contact information
Andrew J. Scott: University of Michigan
Anjali Mittal: University of Michigan
Baharan Meghdadi: University of Michigan
Alexandra O’Brien: University of Michigan
Justine Bailleul: University of California
Palavalasa Sravya: University of Michigan
Abhinav Achreja: University of Michigan
Weihua Zhou: University of Michigan
Jie Xu: University of Michigan
Angelica Lin: University of Michigan
Kari Wilder-Romans: University of Michigan
Ningning Liang: University of Michigan
Ayesha U. Kothari: University of Michigan
Navyateja Korimerla: University of Michigan
Donna M. Edwards: University of Michigan
Zhe Wu: University of Michigan
Jiane Feng: University of Michigan
Sophia Su: University of Michigan
Li Zhang: University of Michigan
Peter Sajjakulnukit: University of Michigan
Anthony C. Andren: University of Michigan
Junyoung O. Park: University of California
Johanna Hoeve: University of California
Vijay Tarnal: University of Michigan
Kimberly A. Redic: University of Michigan
Nathan R. Qi: University of Michigan
Joshua L. Fischer: Bruker Daltonics
Ethan Yang: Bruker Daltonics
Michael S. Regan: Harvard Medical School
Sylwia A. Stopka: Harvard Medical School
Gerard Baquer: Harvard Medical School
Krithika Suresh: University of Michigan
Jann N. Sarkaria: Mayo Clinic
Theodore S. Lawrence: University of Michigan
Sriram Venneti: University of Michigan
Nathalie Y. R. Agar: Harvard Medical School
Erina Vlashi: University of California
Costas A. Lyssiotis: University of Michigan
Wajd N. Al-Holou: University of Michigan
Deepak Nagrath: University of Michigan
Daniel R. Wahl: University of Michigan

Nature, 2025, vol. 646, issue 8084, 413-422

Abstract: Abstract The brain avidly consumes glucose to fuel neurophysiology1. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue2. How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused 13C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid 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 glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

Date: 2025
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DOI: 10.1038/s41586-025-09460-7

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