Rewiring of cortical glucose metabolism fuels human brain cancer growth

Andrew J Scott^#^{1

2}, Anjali Mittal^#^{3

4

5}, Baharan Meghdadi^#^{3

4

5}, Alexandra O'Brien¹, Justine Bailleul^{6

7}, Palavalasa Sravya¹, Abhinav Achreja^{2

3

4

8}, Weihua Zhou^{1

2}, Jie Xu¹, Angelica Lin¹, Kari Wilder-Romans¹, Ningning Liang¹, Ayesha U Kothari¹, Navyateja Korimerla¹, Donna M Edwards¹, Zhe Wu⁹, Jiane Feng⁹, Sophia Su¹, Li Zhang⁹, Peter Sajjakulnukit⁹, Anthony C Andren⁹, Junyoung O Park¹⁰, Johanna Ten Hoeve¹¹, Vijay Tarnal^{12

13}, Kimberly A Redic¹⁴, Nathan R Qi⁹, Joshua L Fischer¹⁵, Ethan Yang¹⁵, Michael S Regan¹⁶, Sylwia A Stopka¹⁶, Gerard Baquer¹⁶, Krithika Suresh^{1

17}, Jann N Sarkaria¹⁸, Theodore S Lawrence^{1

2}, Sriram Venneti¹⁹, Nathalie Y R Agar¹⁶, Erina Vlashi^{6

7}, Costas A Lyssiotis^{20

21

22}, Wajd N Al-Holou^{23

24}, Deepak Nagrath^{25

26

27

28}, Daniel R Wahl^{29

30

31}

Affiliations

¹ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
² Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
³ Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA.
⁴ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁷ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
⁸ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA, USA.
¹¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹² Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Department of Pharmacy Services, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Bruker Daltonics, Billerica, MA, USA.
¹⁶ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
²⁰ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. clyssiot@umich.edu.
²¹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. clyssiot@umich.edu.
²² Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA. clyssiot@umich.edu.
²³ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. wna@med.umich.edu.
²⁴ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA. wna@med.umich.edu.
²⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. dnagrath@umich.edu.
²⁶ Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA. dnagrath@umich.edu.
²⁷ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. dnagrath@umich.edu.
²⁸ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. dnagrath@umich.edu.
²⁹ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. dwahl@med.umich.edu.
³⁰ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. dwahl@med.umich.edu.
³¹ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA. dwahl@med.umich.edu.

^# Contributed equally.

PMID: 40903569
DOI: 10.1038/s41586-025-09460-7

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Andrew J Scott et al. Nature. 2025.

. 2025 Sep 3.

doi: 10.1038/s41586-025-09460-7. Online ahead of print.

Authors

Affiliations

¹ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
² Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
³ Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA.
⁴ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁷ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
⁸ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA, USA.
¹¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
¹² Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Department of Pharmacy Services, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Bruker Daltonics, Billerica, MA, USA.
¹⁶ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
²⁰ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. clyssiot@umich.edu.
²¹ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. clyssiot@umich.edu.
²² Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA. clyssiot@umich.edu.
²³ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. wna@med.umich.edu.
²⁴ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA. wna@med.umich.edu.
²⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. dnagrath@umich.edu.
²⁶ Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA. dnagrath@umich.edu.
²⁷ Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. dnagrath@umich.edu.
²⁸ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. dnagrath@umich.edu.
²⁹ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. dwahl@med.umich.edu.
³⁰ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. dwahl@med.umich.edu.
³¹ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA. dwahl@med.umich.edu.

^# Contributed equally.

PMID: 40903569
DOI: 10.1038/s41586-025-09460-7

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.

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Conflict of interest statement

Competing interests: D.R.W. has consulted for Agios Pharmaceuticals, Admare Pharmaceuticals, Bruker and Innocrin Pharmaceuticals. D.R.W. is listed as an inventor on patents pertaining to the treatment of patients with brain tumours (US provisional patent application 63/416,146, US provisional patent application 62/744,342, US provisional patent application 62/724,337). A.J.S., D.N., C.A.L., A.M., A.A. and B.M. are listed as co-inventors on US provisional patent application 63/416,146. N.Y.R.A. reports the following disclosures: key opinion leader to Bruker Daltonics, collaboration with Thermo Finnigan, service agreement with EMD Serono, service agreement with iTeos Therapeutics, and founder and board member of BondZ. In the past three years, C.A.L. has consulted for Odyssey Therapeutics and Third Rock Ventures. W.N.A.-H. has consulted for Servier Pharmaceuticals. The other authors declare no competing interests.

Update of

Rewiring of cortical glucose metabolism fuels human brain cancer growth.
Scott AJ, Mittal A, Meghdadi B, Palavalasa S, Achreja A, O'Brien A, Kothari AU, Zhou W, Xu J, Lin A, Wilder-Romans K, Edwards DM, Wu Z, Feng J, Andren AC, Zhang L, Tarnal V, Redic KA, Qi N, Fischer J, Yang E, Regan MS, Stopka SA, Baquer G, Lawrence TS, Venneti S, Agar NYR, Lyssiotis CA, Al-Holou WN, Nagrath D, Wahl DR. Scott AJ, et al. medRxiv [Preprint]. 2023 Oct 25:2023.10.24.23297489. doi: 10.1101/2023.10.24.23297489. medRxiv. 2023. Update in: Nature. 2025 Sep 3. doi: 10.1038/s41586-025-09460-7. PMID: 37961582 Free PMC article. Updated. Preprint.

References

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Rewiring of cortical glucose metabolism fuels human brain cancer growth

Affiliations

Rewiring of cortical glucose metabolism fuels human brain cancer growth

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

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Medical