gliomas<\/a> and surrounding neurons contribute to tumour progression, as neuronal activity can stimulate glioma growth and invasion.<\/p>\nTo investigate whether tumour metabolism contributes to this relationship, researchers conducted multi-omics analyses of 91 primary human brain tissue samples, including HGGs, lower-grade gliomas, brain metastases, and non-malignant tissue.<\/p>\n
GAA emerged as a striking metabolic feature, accumulating approximately 100-fold in HGG compared with non-malignant brain. In contrast, creatine and creatinine levels were reduced, indicating that GAA accumulation did not simply reflect increased creatine production.<\/p>\n
Further experiments showed that glioma cells produced and secreted GAA rather than converting it into creatine. This resulted from an imbalance between the creatine synthesis enzymes AGAT and GAMT. Tumour-rich tissue from the glioma margin and core also secreted substantially more GAA than normal-appearing brain tissue.<\/p>\n
Tumours Exploit Neuronal Signalling<\/p>\n
GAA also accumulates in GAMT deficiency, a rare inherited metabolic disorder associated with seizures, prompting researchers to investigate whether glioma-derived GAA could affect neuronal activity.<\/p>\n
Experiments revealed that GAA activated GABA-A receptors. Although this signalling normally inhibits mature neurons, neurons surrounding gliomas have altered chloride regulation, changing their response to GABA-A receptor activation.<\/p>\n
In tumour-infiltrated mouse brain tissue, GAA increased neuronal firing, but this effect was not observed in the opposite, tumour-free hemisphere. The findings suggest that gliomas exploit altered neuronal physiology to convert GAA signalling into an excitatory response.<\/p>\n
Could GAA Become a Therapeutic Target?<\/p>\n
Researchers next genetically removed AGAT, the enzyme responsible for GAA synthesis, from glioblastoma cells. This reduced GAA production without directly affecting tumour-cell growth in laboratory cultures.<\/p>\n
However, mice implanted with AGAT-deficient glioblastoma cells survived longer than those with GAA-producing tumours. GAA depletion also reduced neuronal activity surrounding tumours and decreased tumour\u2013neuron interactions.<\/p>\n
Further experiments showed that GAA increased glioma-cell proliferation by approximately 50% when tumour cells were cultured alongside neurons, but had no effect when tumour cells were cultured alone, highlighting the importance of neuronal involvement.<\/p>\n
The findings identify GAA synthesis as a potential therapeutic target linking cancer metabolism with cancer neuroscience. Further research will be required to establish whether targeting this pathway can safely and effectively treat HGG in humans.<\/p>\n
Reference<\/p>\n
Abdullah KG et al. Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth. Cell. 2026. doi:10.1016\/j.cell.2026.08.037.<\/p>\n
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