Metabolite buildup reveals how aggressive brain tumors activate nearby neurons

by UT Southwestern Medical Center

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Virtually all high-grade, aggressive gliomas in adults accumulate massive amounts of a metabolite called guanidinoacetate (GAA) that overstimulates nearby neurons and promotes tumor growth, according to new research from scientists at Children's Medical Center Research Institute at UT Southwestern (CRI) published in Cell.

Researchers discovered the 100-fold accumulation of GAA occurs when tumors hyperactivate the enzyme that creates GAA. With cancer cells oversaturated, the GAMT enzyme can't convert the extra GAA into creatine. Excess GAA is released into the tumor microenvironment and stimulates neurons that promote tumor growth.

GAA accumulation in these tumors mimics a known inborn error of metabolism called GAMT deficiency that—like high-grade gliomas—results in seizures and neurological symptoms.

"Our work addresses a long-standing question in cancer neuroscience. We knew there is increased activity of neurons in brain tumors, but we had an incomplete understanding of how brain tumors cause that increase in activity," said study leader Samuel McBrayer, Ph.D., assistant professor in CRI and of pediatrics.

Following this discovery, researchers will test whether a clinically approved dietary therapy for GAMT deficiency could block GAA accumulation in patients with high-grade glioma.

"We are going to take these laboratory findings and immediately see how to benefit patients," said Kalil G. Abdullah, M.D., study first author, system director for central nervous system cancer at Northwell Health and former UT Southwestern faculty member. "Our trial will modify the diets of patients before they undergo surgery for a glioma, and we will know very quickly how the diet changes the tumor itself by analyzing brain tumor tissue from their surgery."

If the dietary modification successfully reduces GAA levels in tumors, McBrayer said, subsequent studies could test whether dietary changes improve therapy responsiveness and survival in patients.

GAA drives a neuronal feedback loop

Scientists discovered that when GAA seeps out of cancer cells, it binds to and activates receptors on neurons near the tumor. In response, neurons are stimulated, causing them to release chemical and electrical signals that drive glioma cell proliferation.

In the study, researchers used multiple experiments to show GAA promotes the growth of brain tumors by activating adjacent neurons. When scientists blocked the enzyme making GAA in glioma cells, GAA levels fell, neuronal activity dropped, and tumor growth slowed. If neurons adjacent to brain tumors were activated by other means, neurons promoted tumor growth even in the absence of GAA. Also, when cancer cells were grown in the absence of adjacent neurons, depleting GAA did not slow the proliferation of cancer cells.

"A major benefit of doing research as part of the CRI Genetic and Metabolic Disease Program is that we are able to leverage insights from well-characterized inborn errors of metabolism to understand how metabolism goes awry in brain tumors," McBrayer said. "By comparing these diseases, we are better able to pinpoint the causes and consequences of metabolic changes in glioma, ultimately informing new ways to treat these cancers."

Publication details

Kalil G. Abdullah et al, Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth, Cell (2026). DOI: 10.1016/j.cell.2026.08.037

Journal information: Cell

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OncologyNeurology Provided by UT Southwestern Medical Center Who's behind this story?

Gaby Clark

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