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High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.
High-grade gliomas are the leading cause of central nervous system cancer-related death in both children and adults. This clinical intractability indicates that the current understanding of glioma pathophysiology is insufficient. Gliomas infiltrate extensively within the brain and spinal cord, but growth outside the central nervous system is exceedingly rare. Glioma progression is regulated not only by cell-intrinsic mechanisms, but also by important microenvironmental dependencies. Neurons are a crucial component ofthe glioma microenvironment and regulate malignant growth in an activity-dependent manner1,2. Activity-regulated release of neuroligin-3 (NLGN3)1,2 is required for glioma progression2, indicating a fundamental role in glioma pathophysiology that is incompletely explained by stimulation of classical oncogenic signalling pathways alone2. We previously found that NLGN3 induces glioma expression of numerous synaptic genes2, raising the possibility that glioma may engage in synaptic communication. Synapses exist between neurons and normal oligodendroglial precursor cells (OPCs)3,4, and electrochemical signalling can regulate the proliferation, differentiation or survival of OPCs and of other neural precursor cells5-9. As cellular subpopulations within gliomas closely resemble OPCs10,11, we proposed that gliomas may also engage in synaptic communication and that this integration into neural circuits may be fundamental to glioma progression.
Synaptic gene expression in glioma
To examine synaptic gene expression in primary human glioma, we analysed single-cell transcriptomic datasets generated from pretreatment biopsy samples of the major classes of adult and paediatric high-grade gliomas, including adult isocitrate...