Scientists discover metabolite fueling aggressive brain tumor growth

Researchers discovered the 100-fold accumulation of GAA happens 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 which – just like high-grade gliomas – results in seizures and neurological symptoms.

Samuel McBrayer, Ph.D., Study Leader and Assistant Professor, CRI and of PediatricsOur 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.”

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, Dr. McBrayer said, subsequent studies could test whether dietary change improves therapy responsiveness and survival in patients.

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.

Additional first authors include Charles K. Edgar, Ph.D., Perot Family Scholars Medical Scientist Training Program graduate student at UT Southwestern, Shuangcheng Alivia Wu, Ph.D., CRI postdoctoral fellow, and Yi Xiao, Ph.D., National Institutes of Health Pathway to Independence fellow and CRI postdoctoral fellow, all McBrayer Lab researchers; and Kenji Miki, M.D., postdoctoral fellow at Northwell Health.

This research was funded by the National Institutes of Health, Oligo Nation, Sarkes and Mary Tarzian Charitable Foundation Inc., CPRIT, The Sontag Foundation, Jonesville Foundation, The Nick Gonzales Foundation for Brain Tumor Research, a Human Frontier Science Program fellowship, a Burroughs Wellcome Fund Career Award for Medical Scientists, a Lubin Family Foundation Scholar Award, and the Spanish Ministerio de Ciencia, Innovación y Universidades, and Junta de Andalucía, Consejería de Salud.

Dr. McBrayer has a financial interest in Gliomet.

Source:

UT Southwestern Medical Center