Glutamate receptors found to drive pediatric brain tumor development

The most common type of brain tumor in children, pilocytic astrocytoma (PA), accounts for about 15% of all pediatric brain tumors. Although this type of tumor is usually not life-threatening, the unchecked growth of tumor cells can disrupt normal brain development and function. Current treatments focus mainly on removing the tumor cells, but recent studies have shown that non-cancerous cells, such as nerve cells, also play a role in brain tumor formation and growth, suggesting novel approaches to treating these cancers.

Scientists have long known that a nerve cell signaling chemical called glutamate can increase growth of cancers throughout the body, but despite years of investigation, they haven't figured out exactly how this happens, or how to stop it. Now, an interdisciplinary team of researchers at Washington University School of Medicine in St. Louis has uncovered how glutamate regulates pediatric brain tumor growth. Using tumor cells isolated from patient PA samples, they found that PA cells hijack the function of proteins on cells' surface that normally respond to glutamate, called glutamate receptors. Instead of transmitting glutamate's typical electrical signal, these receptors are reprogrammed to send signals to increase cell growth.

They also observed that drugs that block these glutamate receptors - including memantine, which is approved to treat dementia and Alzheimer's disease - reduced human pediatric brain tumor growth in mice, a finding that points to a potential new treatment opportunity.

The results appear September 1 in Neuron.

With these kinds of pediatric brain tumors, we just don't have that many tools in our toolbox for treating patients. The potential to repurpose drugs that are already in use for other neurological disorders means we may have another trick up our sleeves for treating patients."

David Gutmann, MD, PhD, senior author, the Donald O. Schnuck Family Professor of Neurology at WashU Medicine

The research team, which included first author Corina Anastasaki, PhD, a research assistant professor of neurology at WashU Medicine, also showed for the first time that glutamate receptors abnormally couple with growth receptors in PAs to fuel the tumors. The findings offer a roadmap for future studies to explore if the same process is happening in different types of cancers.

New uses for familiar tools

Glutamate is what is known as a neurotransmitter, a molecule that nerve cells, including neurons in the brain, use to communicate with each other. On their path to understand how glutamate helps brain tumors grow, Gutmann, who is also the director of the Neurofibromatosis Center at WashU Medicine, and Anastasaki worked closely with collaborators across WashU Medicine - including in neurosurgery, pediatrics, genetics, neuropathology, biostatistics and more - to acquire and analyze samples of PAs that had been surgically removed. They found that these PA cells had unusually high levels of glutamate receptors.

By testing how glutamate affected these tumors, the researchers discovered that glutamate increased PA cell numbers by kicking off a chain reaction inside the tumor cells that urged cells to divide. These findings suggest that tumor cells exploit normal brain-cell interactions to spur their own growth.

"This novel mechanism for tumor growth combines two normal but unconnected brain processes - growth and electrical signaling - in an aberrant way," Anastasaki said. "Now that we've figured out how these cells work and grow, the sky's the limit for looking at other neurotransmitters and the different avenues of communication between neurons and cancer cells. Understanding that will tell us why tumors grow and behave the way they do. That may lead to us treating them very differently."

Such new treatments might come from familiar sources. The researchers showed that inhibiting glutamate receptors of tumor cells in mice with PAs - either with medications or by genetically altering the cells - reduced tumor growth. This points to a potential opportunity to repurpose glutamate receptor-targeting drugs such as memantine for the treatment of PAs.

The next steps are to determine whether such medications are safe to use in children with brain tumors and in what amounts they would be effective, Gutmann noted, which will require clinical trials.

"This study provides compelling preclinical data to look at medications that are otherwise safe and approved to treat other neurological conditions," Gutmann said. "That would enable new therapeutic approaches and could help minimize the damage to a child's developing brain by reducing engagement between brain cells and tumor cells."

Anastasaki C, Mu R, Kernan CM, Li X, Barakat R, Koleske JP, Gao Y, Cobb OM, Lu X, Eberhart CG, Phillips JJ, Strahle JM, Dahiya S, Mennerick SJ, Rodriguez FJ, Gutmann D. Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain tumor growth. Neuron. September 1, 2025.