Brain Tumors Manipulate Neurons With a Metabolite; Mechanism Identified in Cell

A study has found that high-grade gliomas, malignant brain tumors, secrete a specific metabolite that excites nearby neurons and thereby promotes their own growth.

A team led by Samuel McBrayer of the University of Texas Southwestern Medical Center published the findings in the journal Cell on the 15th (local time).

The researchers used multiomics techniques to analyze 91 human brain tissue samples and identified a shared metabolic feature in high-grade gliomas: abnormal accumulation of guanidinoacetate (GAA), an intermediate in creatine synthesis, a process involved in energy metabolism in muscle and the brain.

GAA concentrations were about 100 times higher than in normal brain tissue. In normal cells, the enzyme GAMT converts GAA into creatine, but glioma cells had impaired activity of this enzyme and could not convert GAA into creatine, instead secreting it unchanged.

GAA is known to accumulate in GAMT deficiency, a rare genetic disorder, and to cause excessive neuronal excitation. The researchers hypothesized that gliomas secrete large amounts of GAA, putting nearby neurons into a state resembling GAMT deficiency; experiments confirmed the hypothesis.

GAA bound to and activated GABAA receptors on neurons. However, chloride ion homeostasis was disrupted in neurons surrounding the tumor, causing these receptors to generate depolarizing currents rather than inhibitory signals. In effect, inhibitory signals were converted into excitatory signals.

This led to excessive neural network activity, which in turn fueled glioma proliferation and invasion, creating a vicious cycle. In experiments, removing GAA from tumors reduced abnormal neuronal firing and weakened interactions between tumors and neurons, while also markedly reducing tumor invasiveness.

The researchers said the findings provide a link between cancer metabolism and cancer neuroscience. It was already known that “metabolic abnormalities promote glioma growth” and that “interactions with neurons promote glioma growth”; GAA, they said, is a key molecule connecting the two mechanisms.

The researchers suggested that measuring GAA or the activity of related synthesis enzymes could serve as a glioma classification or prognostic marker, and that inhibiting GAA synthesis or blocking GABAA receptors could break the vicious cycle between tumors and neurons.

However, because the evidence comes from tissue analyses and animal models, the researchers added that further validation is needed of the detailed mechanisms by which GAA regulates neural networks over the long term in humans and of the safety of drugs targeting GAA synthesis.