Editors' ChoiceBrain Cancer

Unplugging brain tumor cells

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Science Translational Medicine  09 Oct 2019:
Vol. 11, Issue 513, eaaz3710
DOI: 10.1126/scitranslmed.aaz3710

Abstract

Electrical coupling of brain tumor cells to neurons drives tumor growth.

High-grade gliomas are pervasive tumors of the central nervous system that rely on the activity of neurons to grow and spread. A new study shows glioma cells manage to do so by wiring into the brain in a fashion akin to how neurons connect with each other.

Mining through single-cell gene expression data of several types of pediatric and adult gliomas, Venkatesh and colleagues investigated the mechanisms mediating tumor growth. The authors showed that glioma cells expressed several proteins typically found on the postsynaptic end of a connection between two neurons. Via ultrastructural electron microscopy of human glioma cells transplanted into mouse brains, they estimated that around 10% of the transplanted glioma cells formed what looked like synapses with mouse neurons. These synapses were active and had the electrical properties of excitatory synapses that depend upon the neurotransmitter glutamate, which induced a depolarization of the glioma cell membranes. Moreover, glioma cells were responsive to neuron activity through a mechanism which did not involve synapses, and which propagated through gap junctions connecting adjacent glioma membranes. Interestingly, when the scientists engineered glioma cells to electrically activate in response to light, glioma cells proliferated more avidly. Genetically manipulating glioma cells to be more readily excitable had similar effects and killed recipient mice faster. On the contrary, pharmacologically preventing glioma cell electrical activation with a glutamate receptor inhibitor or a gap junction blocker slowed tumor cell proliferation. Lastly, and supporting the idea that neuron and glioma cell communication is bidirectional, three adult patients undergoing clinical glioma resection presented heightened neural activity in areas where the tumors had infiltrated, suggesting glioma cells may render neurons more excitable to further promote their own growth.

Characterizing the tumor heterogeneity from the perspective of its electrical activity and singling out electrical properties that confer glioma cells a growth advantage requires a more comprehensive analysis. Moreover, more mechanistic work is needed to elucidate the molecular pathways mediating the connectivity between glioma cells and neurons. Meanwhile, the prospect that brain tumor therapy could be approached with drugs already used in the clinic to dampen neuronal excitability, such as the anti-epileptic drug used in this study, is exciting and grants further consideration of this therapeutic avenue.

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