High-grade gliomas release a metabolite that excites nearby neurons and promotes tumour growth

What happened

Metabolomics on human brain tissue showed that guanidinoacetate (GAA), an intermediate in creatine synthesis, accumulated about 100-fold in high-grade gliomas compared with controls, because of imbalanced enzyme activity in that pathway. Glioma cells secreted the GAA instead of converting it to creatine.

GAA also builds up in GAMT deficiency, an inherited metabolic disorder in which it raises neuronal excitability. The researchers hypothesised that tumour-made GAA excites surrounding neurons, and found that it did: GAA induced hyperactivity by activating GABA-A receptors, which produced depolarising currents in glioma-associated neurons whose chloride balance was disturbed. Depleting GAA in tumours decreased electrochemical activity, neuron–glioma interactions and tumour aggressiveness.

Why it matters

Neuronal activity is known to drive glioma growth, but how tumours raise that activity was incompletely understood. This identifies a tumour-derived metabolite as one cause, linking cancer metabolism to cancer neuroscience. According to UT Southwestern's press release, the researchers plan to test whether a dietary therapy already approved for GAMT deficiency can block GAA accumulation in patients with high-grade glioma.

Caveats

This entry is based on the abstract and the university's press release; the full text was not read. Neither says which laboratory models were used for the depletion experiments, so the evidence level given here is conservative. No treatment has been tested in patients, and whether lowering GAA changes outcomes in people is unknown. The press release states that Samuel McBrayer has a financial interest in Gliomet.