TMET-34. A Targetable Metabolic Signal Drives Neuronal Hyperexcitability and Glioma Aggressiveness

Abstract Our knowledge of the metabolic alterations that modulate glioma-neuron interactions is limited. Therefore, we performed unbiased metabolite profiling on 91 tissue samples, including high grade gliomas, lower grade gliomas, brain metastases, and non-malignant brain specimens. 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. Indeed, 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 activated GABAA receptors. Although GABA signaling is inhibitory in the normal 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, inhibiting GAA production in orthotopic xenografts reduced neuronal activity markers in the tumor microenvironment 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.

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Journal
Neuro-Oncology
Published
2025-11-01
DOI
https://doi.org/10.1093/neuonc/noaf201.1725
Primary Topic
Cancer, Hypoxia, and Metabolism
Type
article
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article

TMET-34. A Targetable Metabolic Signal Drives Neuronal Hyperexcitability and Glioma Aggressiveness

Namya Manoj, Yuan-Tai Huang, Samuel K. McBrayer, Milan R. Savani et al.
Neuro-Oncology
Cancer, Hypoxia, and Metabolism
article

TMET-34. A Targetable Metabolic Signal Drives Neuronal Hyperexcitability and Glioma Aggressiveness

Namya Manoj, Yuan-Tai Huang, Samuel K. McBrayer, Milan R. Savani, Min D. Tang‐Schomer, Jeffrey I. Traylor, Diana D. Shi, Jay R. Gibson, Thomas P. Mathews, Kimberly M. Huber, Alexander Ksendzovsky, Simon Chamberland, Thomas Nolin, Pranita Kaphle, William H. Hicks, Lauren G. Zacharias, Raymond E. West, Tracey Shipman, Shawn E. Kotermanski, Pascal Olivier Zinn, Kalil G. Abdullah, Shuangcheng Alivia Wu, Vineshkumar Thidil Puliyappadamba, Yi Xiao, Kenji Miki, Shihong Ma, Bailey Smith, Maged T. Ghoche, Ralph J. DeBerardinis, Skyler Oken, Charles K. Edgar
article en

Abstract

Abstract Our knowledge of the metabolic alterations that modulate glioma-neuron interactions is limited. Therefore, we performed unbiased metabolite profiling on 91 tissue samples, including high grade gliomas, lower grade gliomas, brain metastases, and non-malignant brain specimens. 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. Indeed, 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 activated GABAA receptors. Although GABA signaling is inhibitory in the normal 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, inhibiting GAA production in orthotopic xenografts reduced neuronal activity markers in the tumor microenvironment 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.

Neuro-OncologyVol. 27(Supplement_5)
University of Maryland, Baltimore (US), Brigham and Women's Hospital (US), Children's Medical Center (US), Howard Hughes Medical Institute (US), Harvard University (US), University of Pittsburgh (US), Southwestern Medical Center (US), Dana-Farber Cancer Institute (US), UPMC Hillman Cancer Center (US), University of Pittsburgh Medical Center (US), Neurological Surgery (US), Dana-Farber Brigham Cancer Center (US), The University of Texas Southwestern Medical Center (US)
Openalex Percentile: Top 59%
Cancer, Hypoxia, and Metabolism
DOIOpen Access PDFOpenAlex
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