2. Academic Validation
  3. Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth

  • bioRxiv. 2025 Sep 18:2025.09.15.676412. doi: 10.1101/2025.09.15.676412.
Kalil G Abdullah,  Kenji Miki,  Charles K Edgar,  Shuangcheng Alivia Wu,  Yi Xiao,  Milan R Savani,  Maged T Ghoche,  Shawn E Kotermanski,  Yuan-Tai Huang,  Jeffrey I Traylor,  Lei Guo,  Kathryn Gunn,  William H Hicks,  Diana D Shi,  Min Tang,  Michael M Levitt,  Mohamad El-Shami,  Skyler Oken,  Namya Manoj,  Bailey C Smith,  Vinesh T Puliyappadamba,  Pranita Kaphle,  Tracey Shipman,  Raymond E West,  Chaoying Liang,  Toral R Patel,  Kimmo J Hatanpaa,  Prithvi Raj,  Shang Ma,  Alexander Ksendzovsky,  Thomas D Nolin,  Bradley C Lega,  Pascal O Zinn,  Bianca J Kuhn,  Natalie M Clark,  C Williams,  D R Mani,  Michael A Gillette,  Marco A Calzado,  Lin Xu,  Lauren G Zacharias,  Feng Cai,  Thomas P Mathews,  Julie-Aurore Losman,  Timothy E Richardson,  Benjamin Levi,  Michelle Monje,  Jay R Gibson,  Osaama H Khan,  Sameer Agnihotri,  Kimberly M Huber,  Simon Chamberland,  Ralph J DeBerardinis,  Samuel K McBrayer
PMID: 41000912 DOI: 10.1101/2025.09.15.676412
Abstract

The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of Enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an unexpected function. GAA accumulates in GAMT deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABA A receptors and causing depolarizing GABA currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a new mechanism linking Cancer metabolism with Cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

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