Neuronal acid-sensing ion channel 1a regulates neuron-to-glioma synapses

Abstract

Neuronal activity promotes high-grade glioma progression via secreted proteins and neuron-to-glioma synapses, and glioma cells boost neuronal activity to further reinforce the malignant cycle. Whereas strong evidence supports that the activity of neuron-to-glioma synapses accelerates tumor progression, the molecular mechanisms that modulate the formation and function of neuron-to-glioma synapses remain largely unknown. Our recent findings suggest that a proton (H+) signaling pathway actively mediates neuron-to-glioma synaptic communications by activating neuronal acid-sensing ion channel 1a (Asic1a), a predominant H+receptor in the central nervous system (CNS). Supporting this idea, our preliminary data revealed that local acid puff on neurons in high-grade glioma-bearing brain slices induces postsynaptic currents of glioma cells. Stimulating Asic1a knockout (Asic1a-/-) neurons results in lower AMPA receptor-dependent excitatory postsynaptic currents (EPSCs) in glioma cells than stimulating wild-type (WT) neurons. Moreover, glioma-bearing Asic1a-/-mice exhibited reduced tumor size and survived longer than the glioma-bearing WT mice. Finally, pharmacologically targeting brain Asic1a inhibited high-grade glioma progression. In conclusion, our findings suggest that the neuronal H+-Asic1a axis plays a key role in regulating the neuron-glioma synapse. The outcomes of this study will greatly expand our understanding of how this deadly tumor integrates into the neuronal microenvironment.

Acid-sensing ion channels and downstream signalling in cancer cells: is there a mechanistic link?

“…Interestingly, a recent study, which has not yet been peerreviewed, reported reduced tumour growth and prolonged survival of mice after transplanting the murine glioma cell line GL261 into the brain of mice with ASIC1a gene deletion [59]. Importantly, ASIC had been knocked-out in the host tissue and not in the tumour cells.…”

“…ASIC expression in GL261 cells was not assessed. The authors proposed that the acidic TME increased ASIC signalling also in neighbouring neurons leading to an increased connectivity between neurons and glioma [59], which is known to drive glioma progression [77][78][79]. However, the mechanisms and signalling pathways underlying this regulatory role of ASIC1a on neuron-glioma connectivity remained unclear.…”