Summary: A new University of Michigan study shows that glioblastoma, the most aggressive form of brain cancer, rewires how it uses glucose. While healthy brain tissue channels sugar into energy and neurotransmitter production, glioblastoma diverts glucose toward creating the building blocks of DNA and RNA, supporting rapid tumor growth and invasion.
Using labeled glucose in both patients and mouse models, researchers traced how carbon from sugar is routed inside healthy cortex versus tumor tissue. The team found that tumors suppress normal glucose-driven brain functions and instead repurpose glucose for biosynthesis. Importantly, restricting specific amino acids in the blood improved responses to radiation and chemotherapy in mice, suggesting a potential metabolic therapy approach that could complement current treatments.
Key Facts
- Metabolic fork: Healthy cortex uses glucose for energy and neurotransmitters; glioblastoma redirects glucose into nucleotide synthesis to fuel proliferation.
- Dietary strategy: Reducing serine and glycine in mouse diets improved tumor response to radiation and chemotherapy.
- Clinical potential: The findings support exploring metabolic interventions—such as diet modulation and targeted drugs—as adjuncts to glioblastoma therapy.
Source: University of Michigan
Overview
Glioblastomas are among the deadliest malignant brain tumors; most patients survive only one to two years after diagnosis. These tumors arise when brain cells abandon normal physiology, proliferating rapidly and infiltrating surrounding tissue. The new study demonstrates that this change in behavior is accompanied by a dramatic metabolic shift: tumors stop using glucose for the brain’s usual functions and instead channel it into biosynthetic pathways that support tumor growth.
Published in Nature, the study represents a collaboration across the Rogel Cancer Center, the Department of Neurosurgery, and the Department of Biomedical Engineering at the University of Michigan. The researchers combined metabolic tracing in patients and mice, quantitative flux analysis, and mathematical modeling to map how glucose-derived carbon and nitrogen are allocated in tumor versus normal cortex.
Distinct glucose use in healthy cortex versus glioblastoma
Metabolism describes how cells break down nutrients and assemble molecules needed for function and growth. Both healthy brain tissue and tumors consume glucose avidly, but they do so for different purposes. In the normal cortex, glucose fuels the tricarboxylic acid (TCA) cycle for energy and supports neurotransmitter synthesis required for cognition and neural signaling. In glioblastoma, those pathways are downregulated. Instead, tumors reroute glucose-derived carbons into nucleotide production and other biosynthetic routes that enable proliferation and invasion.
To reach these conclusions, the team infused 13C-labeled glucose into patients and mice with brain tumors and then measured isotope incorporation into metabolites. Those direct measurements revealed a clear “metabolic fork in the road”: cortex and tumor tissue use the same substrate—glucose—but divert its carbon into sharply different biochemical outcomes.
Amino-acid restriction improves treatment response in mice
Beyond glucose routing, the researchers discovered that normal brain tissue uses glucose to synthesize certain amino acids, while glioblastoma tumors largely scavenge amino acids from the circulation instead of making them internally. This observation suggested a vulnerability: lowering specific amino acids in the blood might hinder tumor growth while sparing normal brain metabolism.
In mouse models, diets lacking the amino acids serine and glycine enhanced the effectiveness of radiation and chemotherapy. Mice fed diets without serine and glycine showed smaller tumors and stronger treatment responses compared with control-fed mice. These experimental results were paired with computational models that track how glucose flows through metabolic pathways, helping to identify promising enzymatic targets for future drugs.
Co-senior authors compared metabolic pathways to roads: blocking a high-traffic metabolic “freeway” used by tumors is more likely to stall cancer growth than obstructing a low-traffic route used by healthy tissue. Because glioblastoma relies heavily on circulating serine and glycine, restricting those amino acids creates a selective pressure that preferentially affects tumor cells.
The research team is preparing to open clinical trials to test whether lowering circulating serine through specialized diets or pharmacologic means can safely alter glioblastoma metabolism in patients and improve outcomes when combined with standard therapies.
“This is a multidisciplinary effort from across the university,” said Daniel Wahl, M.D., Ph.D., co-senior author. “No single investigator could have completed this work alone. We hope these findings will lead to new strategies that enhance treatment for patients with this devastating disease.”
Additional authors: Anjali Mittal, Baharan Meghdadi, Alexandra O’Brien, Justine Bailleul, Sravya Palavalasa, 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 ten 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 and Erina Vlashi.
Funding and disclosures: The study received support from multiple sources including the National Cancer Institute, National Institute of Neurological Disorders and Stroke, Damon Runyon Cancer Foundation, Sontag Foundation, Ivy Glioblastoma Foundation, Forbes Institute for Cancer Discovery, Alex’s Lemonade Stand Foundation, and others. Several investigators have disclosed consulting roles, patents, or collaborations with industry; specific disclosures and provisional patent applications are listed by the authors.
About this glioblastoma research
Author: Ananya Sen
Source: University of Michigan
Contact: Ananya Sen – University of Michigan
Image: The image is credited to Neuroscience News
Original Research: Open access. Title: “Rewiring of cortical glucose metabolism fuels human brain cancer growth” by Daniel Wahl et al., published in Nature. DOI: dx.doi.org/10.1038/s41586-025-09460-7
Abstract (summary)
The brain consumes glucose to support neurophysiology. Glioblastoma abandons normal physiological roles to prioritize proliferation and invasion. By infusing 13C-labeled glucose into patients and mice and performing comprehensive metabolic flux analysis, the authors mapped distinct glucose fates in cortex versus tumor. The human cortex channels glucose into TCA cycle oxidation and neurotransmitter synthesis, while gliomas downregulate those pathways and scavenge alternative carbon and nitrogen sources—repurposing glucose carbons for nucleotide and biomass synthesis. Modulating dietary amino acids in mice selectively altered tumor metabolism, slowed growth, and increased sensitivity to standard therapies. These results reveal how aggressive brain tumors exploit glucose and point to metabolic strategies that may improve treatment outcomes.