Abstract 6802: Metabolite signaling drives oncogenic neuron-glioma crosstalk

Abstract Our knowledge of the metabolic alterations that modulate glioma-neuron interactions is limited. Therefore, we performed unbiased metabolite profiling on 91 high grade gliomas, lower grade gliomas, brain metastases, and non-malignant brain tissues. Accumulation of guanidinoacetate (GAA), an intermediate in the creatine synthesis pathway, was a hallmark of high grade gliomas, displaying a nearly 100-fold increase in these tumors versus non-malignant brain tissues. However, creatine and related metabolites were not enriched, suggesting that GAA may play a non-canonical role. We found that glioma stem-like cell (GSC) lines robustly synthesize GAA but secrete this metabolite rather than using it to produce creatine. This finding has a correlate in GAMT deficiency, an inborn error of metabolism in which GAA accumulates and causes neuronal hyperexcitability, neurological deficits, and seizures. These effects are also observed in glioma patients, but the mechanisms underlying neuronal hyperactivity in this context are not fully understood. We hypothesized that high grade gliomas reprogram the creatine synthesis pathway to generate and release GAA, which signals to surrounding neurons, drives local electrochemical activity and promotes glioma aggressiveness. We found that GAA accumulation excites local, but not distal, neurons in xenografted brain slices. In patch-clamp recording studies, GAA decreased neuronal input resistance by acting as a GABAA receptor agonist. Although GABA signaling is inhibitory in the adult brain, we found that chloride dysregulation in the glioma microenvironment triggers excitatory GABAergic neurotransmission in response to GAA stimulation. Treating glioma-infiltrated brain tissue with a KCC2 chloride transporter agonist abolished GAA-induced hyperexcitability. Although genetic ablation of GAA synthesis had no effect on GSCs grown in vitro or in subcutaneous xenografts, inhibiting GAA production in orthotopic xenografts reduced local neuronal activity and extended survival of tumor-bearing mice. Collectively, our work nominates GAA as a targetable signaling metabolite that drives oncogenic crosstalk between glioma cells and neurons. Citation Format: Kalil G. Abdullah, Kenji Miki, Charles Edgar, Shuangcheng Wu, Yi Xiao, Milan R. Savani, Maged T. Ghoche, Jeffrey I. Traylor, Huang Yuan-Tai, Diana D. Shi, Min Tang, Skyler Oken, Namya Manoj, Vinesh T. Puliyappadamba, Pranita Kaphle, Tracey Shipman, Raymond E. West, Shang Ma, Thomas Nolin, Pascal O. Zinn, Lauren G. Zacharias, Thomas P. Mathews, Jay Gibson, Kimberly Huber, Simon Chamberland, Ralph J. DeBerardinis, Samuel K. McBrayer. Metabolite signaling drives oncogenic neuron-glioma crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6802.