Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Yuan-Tai Huang, Richard Drexler, Saritha Krishna, Vinesh T Puliyappadamba, Li Wei Rachel Tay, Fanen Yuan, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Belgin Yalçın, Kim Kilian, Min Tang, Mitchell Moyer, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Lauren C Gattie, Bailey C Smith, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Yasmina Eshac, Tzu-Yi Chia, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Jason M Miska, Denise M O Ramirez, Shang Ma, 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, Alexander Ksendzovsky, Thomas P Mathews, Julie-Aurore Losman, Benjamin Levi, Tara Barron, Jay R Gibson, Timothy E Richardson, Osaama H Khan, Sameer Agnihotri, Shawn L Hervey-Jumper, Simon Chamberland, Michelle Monje, Kimberly M Huber, Ralph J DeBerardinis, Samuel K McBrayer
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 alternative function. GAA accumulates in GAA N-methyltransferase (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 GABAA receptors and causing depolarizing 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 mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.