Researchers have found that mind most cancers cells reprogram their sugar metabolism, a vulnerability that may be exploited in mice to impede tumor development and improve therapeutic outcomes.
Glioblastomas are essentially the most aggressive sort of malignant mind tumor, and sufferers recognized with this situation sometimes survive just one to 2 years.
Inside these tumors, odd mind cells change their habits, multiplying rapidly and spreading into close by tissue. Not like wholesome mind cells, the cancerous cells course of vitamins in a basically completely different method.
In a current research revealed in Nature, scientists on the College of Michigan, together with consultants from the Rogel Most cancers Heart, the Division of Neurosurgery, and the Division of Biomedical Engineering, investigated how glioblastoma cells metabolize glucose.
Their findings revealed that these tumors depend on distinct nutrient pathways in comparison with regular mind tissue, providing new perception into potential therapy methods.
“We altered the food regimen in mouse fashions and have been ready considerably decelerate and block the expansion of those tumors,” mentioned co-senior writer Daniel Wahl, M.D., Ph.D., affiliate professor of radiation oncology.
“Our research could assist create new therapy alternatives for sufferers within the close to future.”
Typical remedies encompass surgical procedure adopted by radiation remedy and chemotherapy. Nonetheless, the tumors ultimately return and grow to be immune to therapy.
Beforehand, researchers have proven that resistance is because of metabolic rewiring inside most cancers cells.
Most cancers cells within the mind use sugars in a different way in comparison with wholesome cells
Metabolism is the method by which our our bodies break down molecules like carbohydrates and proteins in order that our cells can both use them or construct new molecules.
Though each mind and most cancers cells rely on sugar, the group wished to see in the event that they use sugar in a different way.
They injected small quantities of labelled sugar into mice and, importantly, into sufferers with mind tumors to comply with how it’s used.
“To essentially perceive these mind cancers and enhance remedies for sufferers, we wanted to do the exhausting work of learning the tumors in sufferers themselves, not simply within the lab,” mentioned co-senior writer Wajd Al-Holou, M.D., a mind tumor neurosurgeon who co-directs the Michigan Multidisciplinary Mind Tumor Clinic.
Though each regular tissues and tumor cells used lots of sugar, they used it for various functions.
“It’s a metabolic fork within the highway,” mentioned Andrew Scott, Ph.D., a analysis scholar in Wahl’s lab.
“The mind channels sugar into vitality manufacturing and neurotransmitters for pondering and well being, however tumors redirect sugar to make supplies for extra most cancers cells.”
The group discovered that wholesome tissues used sugars to generate vitality and make chemical substances that permit the mind to operate correctly.
Glioblastomas, then again, turned off these processes and as an alternative transformed sugar into molecules like nucleotides—the constructing blocks of DNA and RNA—that helped them grow and invade the surrounding tissues.
Amino-acid restricted diets can improve treatment outcomes in mice
The researchers also noticed other important differences.
The normal brain used sugar to make amino acids, the building blocks of proteins. However, brain cancers seemed to turn this pathway off and instead scavenged these amino acids from the blood.
This finding led the researchers to consider whether lowering the levels of certain amino acids in the blood could affect brain cancer without affecting the normal brain.
They tested whether mice that were fed an amino acid-restricted diet had better treatment outcomes.
“When we got rid of the amino acids serine and glycine in the mice, their response to radiation and chemotherapy was better and the tumors were smaller than the control mice that were fed serine,” said co-senior author Deepak Nagrath, Ph.D. professor of biomedical engineering.
Based on their measurements in mice, the team also built mathematical models that can track how glucose is being used in different pathways, which can help identify other drug targets.
Co-senior author Costas Lyssiotis, Ph.D., professor of molecular and integrative physiology, compared metabolic pathways to roads and drugs to roadblocks.
Dropping a roadblock on a fast highway with a lot of traffic will have a greater effect than blocking a country road with a lower speed limit and only a few cars.
Similarly, in a normal brain, the uptake of the amino acid serine from the blood is like a slow country road.
But brain cancer is like a busy freeway, giving researchers the opportunity to selectively target the cancer.
The team is working on opening clinical trials soon to test whether specialized diets that limit blood serine levels can also help glioblastoma patients.
“This is a multidisciplinary effort from across the university,” Wahl said.
“It is a study that no individual investigator could do on their own and I’m grateful to be part of a team that works together to make important discoveries that can improve treatments for our patients.”
Reference: “Rewiring of cortical glucose metabolism fuels human brain cancer growth” by 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 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, Erina Vlashi, Costas A. Lyssiotis, Wajd N. Al-Holou, Deepak Nagrath and Daniel R. Wahl, 3 September 2025, Nature.
DOI: 10.1038/s41586-025-09460-7
Funding/disclosures: Scott was supported by the National Cancer Institute (K99CA300923; F32CA260735). Wahl was supported by NCI (K08CA234416; R37CA258346), National Institute of Neurological Disorders and Stroke (R01NS129123), Damon Runyon Cancer Foundation, Sontag Foundation, Ivy Glioblastoma Foundation, Forbes Institute for Cancer Discovery, Alex’s Lemonade Stand Foundation and Chad Tough Defeat DIPG foundation. Wahl and Lawrence were supported by NCI P50CA269022. Nagrath was supported by NCI (R01CA271369). Wu, Feng and Qi were supported by NIDDK MMPC-Live (1U2CDK135066). Zhou was supported by University of Michigan Medical School’s Pandemic Research Recovery grant (U083054). Al-Holou was supported by NINDS (K08NS12827101), American Cancer Society (CSDG-23-1031584-01-MM), and American Brain Tumor Association. Palavalasa was supported by American Cancer Society (PF-23-1077428-01-MM). Venneti was supported by NINDS (R01NS110572 and R01NS127799) and NCI (R01CA261926). Vlashi and Bailleul were supported by NCI (CA251872 and CA251872-S1). Bailleul was supported by a UCLA JCCC Fellowship Award. Park was supported by the National Institute of General Medical Sciences (R35GM143127). Sarkaria was supported by Mayo Clinic and the William H. Donner Professorship. Agar was supported by the Daniel E. Ponton Fund, National Brain Tumor Society, Mass Life Sciences Center, and NCI(U54CA283114).
Tech transfer(s)/Conflict(s) of interest: Wahl has consulted for Agios Pharmaceuticals, Admare Pharmaceuticals, Bruker and Innocrin Pharmaceuticals. He is an inventor on patents pertaining to the treatment of patients with brain tumors (U.S. Provisional Patent Application 63/416,146, U.S. Provisional Patent Application 62/744,342, U.S. Provisional Patent Applicant 62/724,337). Scott, Nagrath, Lyssiotis, Mittal, Achreja and Meghdadi are co-inventors on U.S. Provisional Patent Application 63/416,146. In the past three years, Lyssiotis has consulted for Odyssey Therapeutics and Third Rock Ventures. Al-Holou has consulted for Servier Pharmaceuticals. Agar 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.
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