美国得克萨斯大学西南医学中心儿童医学中心研究所Samuel K. McBrayer团队近日取得一项新成果。经过不懈努力，他们研究出神经胶质瘤表型是一种先天的代谢错误，以驱动神经元活动和肿瘤生长。该研究于近日发表于国际一流学术期刊《细胞》杂志上。
高级别胶质瘤（HGG）的代谢特征尚未被完全理解。人类脑组织代谢组学显示，与对照相比，HGG中肌酸合成通路中间体胍乙酸（GAA）积累约100倍，这是由该通路中酶活性的失衡引起的。胶质瘤细胞分泌GAA，而不是用它来产生肌酸，提示其具有另一种功能。GAA在GAA N-甲基转移酶（GAMT）缺乏症——一种先天性代谢缺陷——中积累，并提高神经元兴奋性。胶质瘤中的神经元兴奋性也增加，并通过神经元-胶质瘤相互作用驱动肿瘤生长。研究人员假设，胶质瘤产生的GAA会兴奋周围神经元。确实，GAA通过激活GABAA受体，并在氯稳态失调的胶质瘤相关神经元中引起去极化电流，从而诱导神经元过度活跃。耗竭肿瘤GAA可降低电化学活动、神经元-胶质瘤相互作用和肿瘤侵袭性。研究人员的发现揭示了一种将癌症代谢与癌症神经科学联系起来的机制，并利用人类遗传学提出GAA合成作为胶质瘤的靶点。
附：英文原文
Title: Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth
Author: 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 Yaln, 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
Issue&Volume:
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 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.
DOI: 10.1016/j.cell.2026.08.037
Source: https://www.cell.com/cell/abstract/S0092-8674(26)01010-X