The researchers achieved a scientific first: mapping the precise fate of glucose-derived carbon atoms in both tumor and neighboring healthy brain (cortex) tissue using advanced mass spectrometry and metabolic modeling.
How does one of the most aggressive cancers in the human body, glioblastoma (GBM), fuel its relentless growth? A pioneering interdisciplinary study published in Nature and co-led by Deepak Nagrath, Ph.D., Professor, Biomedical Engineering and Chemical Engineering, Daniel Wahl, M.D., Ph.D., Achtenberg Family Professor of Radiation Oncology, Associate Professor of Radiation Oncology and Neurosurgery, Medical School, Wajd Al-Holou, M.D., Assistant Professor, Neurosurgery, and Costas Lyssiotis, Professor, Physiology and Medicine, is helping answer this question. Their research findings open the door to the possibility of entirely new therapeutic approaches in treating and managing brain cancer.
Peering Inside Tumor Metabolism
Traditionally, cancer metabolism research has required taking cells out of their natural habitat, growing them in petri dishes far removed from the biological reality of a living brain. “In vivo, or within the brain, is very difficult,” Dr. Nagrath explained. “What are the nutrients that [tumors] utilize? What are they dependent on?”
To tackle this challenge, the research team infused patients with a safe, non-radioactive version of glucose—an essential sugar molecule labeled with “heavy” carbon atoms—during brain surgery for GBM. “We have infused this 13-carbon labeled glucose, and through that, and dissecting the metabolism and quantitative models, we are able to understand how these cancer cells utilize glucose,” said Dr. Wahl.
With this approach, the researchers achieved a scientific first: mapping the precise fate of glucose-derived carbon atoms in both tumor and neighboring healthy brain (cortex) tissue using advanced mass spectrometry and metabolic modeling. This allowed direct, real-time tracking of how tumors ‘choose’ to use nutrients as compared to normal brain cells.
Repurposing Glucose for Growth
What’s the difference between healthy brain cells and tumor cells in using food for fuel? According to Baharan Meghdadi, a co-leading author in the study, “In the human cortex, glucose carbons fuel essential physiologic processes including TCA cycle oxidation and neurotransmitter synthesis.” Healthy brain cells mostly use glucose to create energy for normal physiology—powering thoughts, movement, and repair.
But brain cancers, especially GBM, have a different agenda. “Gliomas reroute these glucose carbons to produce nucleotides, which are building blocks for proliferation and can be used to resist treatment. That has been a major finding,” Andrew Scott, Ph.D., Research Fellow, Radiation Oncology, and a co-leading author of the study, noted.
In effect, these tumors hijack glucose not to help the brain work, but to build the molecular “building blocks” (nucleotides) needed for copying DNA and rapid growth—“malignant expansion” rather than normal activity.
Can Diet Make a Difference? Examining Serine Restriction
One of the most exciting findings ties metabolism to diet—a concept with significant translational potential. The team’s studies in mice showed that restricting the dietary supply of serine, a common amino acid, significantly reduced the ability of tumor cells to generate nucleotides and slowed tumor growth. Importantly, “it doesn’t affect the normal area, cortex metabolites, so that was our finding,” said Dr. Nagrath. “That means that the serine-depleted diet, or dietary serine restriction, could be extremely beneficial.”
This insight is already being translated into action. The research team is collaborating with clinicians and specialized nutrition companies to initiate a serine-restricted diet clinical trial for patients with GBM at Michigan Medicine. Dr. Wahl is hopeful that the study—which forms part of a new multi-year National Institutes of Health (NIH) grant—will launch within the next couple of years, integrating precision dietary intervention with standard radiation and chemotherapy.
“To remove the amino acid [serine] isn’t easy, so it takes a proprietary, pre-made diet from the company,” Dr. Nagrath explained. “But if it provides some promise of reducing tumor growth, or shrinking [the tumor], certainly that would be an amazing discovery.”
A New Frontier for Brain Cancer Therapy
GBM is known for its devastating prognosis and resistance to existing treatments. “Most patients die within 1-2 years of diagnosis,” said Dr. Nagrath, pointing to the pressing need for new, personalized approaches. By directly comparing tumor and healthy brain metabolism in patients—and uncovering a metabolic “Achilles’ heel” in glucose and amino acid handling—Dr. Nagrath and his U-M colleagues are providing promising new strategies to slow or stop tumor progression.
“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,” the team report noted.
Please read details of the complete study here.