Rewiring of cortical glucose metabolism fuels human brain cancer growth

• 成果类型: Article
• 署名作者: Scott, Andrew J.; Mittal, Anjali; Meghdadi, Baharan; O'Brien, Alexandra; Bailleul, Justine; Sravya, Palavalasa; Achreja, Abhinav; Zhou, Weihua; Xu, Jie; Lin, Angelica; Wilder-Romans, Kari; Liang, Ningning; Kothari, Ayesha U.; Korimerla, Navyateja; Edwards, Donna M.; Wu, Zhe; Feng, Jiane; Su, Sophia; Zhang, Li; Sajjakulnukit, Peter; Andren, Anthony C.; Park, Junyoung O.; ten Hoeve, Johanna; Tarnal, Vijay; Redic, Kimberly A.; Qi, Nathan R.; Fischer, Joshua L.; Yang, Ethan; Regan, Michael S.; Stopka, Sylwia A.; Baquer, Gerard; Suresh, Krithika; Sarkaria, Jann N.; Lawrence, Theodore S.; Venneti, Sriram; Agar, Nathalie Y. R.; Vlashi, Erina; Lyssiotis, Costas A.; Al-Holou, Wajd N.; Nagrath, Deepak; Wahl, Daniel R.
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of California System; University of California Los Angeles; David Geffen School of Medicine at UCLA; University of California Los Angeles Medical Center; University of California System; UCLA Jonsson Comprehensive Cancer Center; University of California Los Angeles; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; David Geffen School of Medicine at UCLA; University of California Los Angeles Medical Center; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Bruker Corporation; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of Michigan System; University of Michigan; Mayo Clinic; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09460-7
• 发表日期: 2025-10-09
• 关键词: mouse model; isotopomer distributions; cell-survival; tca cycle; in-vivo; serine; tumor; acetate; identification; Heterogeneity

摘要

The brain avidly consumes glucose to fuel neurophysiology1. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue2. How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused 13C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.