Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion

Abstract

SUMMARY Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.

Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma

“…Conditioned medium (CM) from optogenetically-stimulated acute cortical slices from Nlgn3 WT or KO; Thy1::ChR2 mice demonstrated that the increase in glioma cell proliferation induced by active CM is incompletely abrogated in the context of Nlgn3 KO (Extended Data Fig. 2a), replicating the degree of differential proliferation previously accounted for by activity-regulated Bdnf 1 . Taken together, these findings indicate that glioma growth is more dependent on neuroligin-3 in vivo than would have been predicted from these in situ / in vitro experiments.…”

“…We found no effect of NLGN1, NLGN4X/Y (Extended Data Fig. 2b,c) or NLGN2 1 on glioma proliferation. Thus, compensatory expression of other neuroligins would not be expected to influence glioma growth, supporting a unique role for NLGN3 in glioma pathobiology.…”

“…1c,d). The observed degree of growth inhibition was unexpected, as our previous work indicated that brain-derived neurotrophic factor (BDNF) also contributes to activity-regulated glioma proliferation 1 . Conditioned medium (CM) from optogenetically-stimulated acute cortical slices from Nlgn3 WT or KO; Thy1::ChR2 mice demonstrated that the increase in glioma cell proliferation induced by active CM is incompletely abrogated in the context of Nlgn3 KO (Extended Data Fig.…”

“…Therapies aimed at mechanisms intrinsic to the glioma cell have translated to only limited success; effective therapeutic strategies will need to also target elements of the tumor microenvironment that promote glioma progression. We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG) 1 . An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway 1 .…”

“…We recently demonstrated that neuronal activity robustly promotes the growth of a range of molecularly and clinically distinct HGG types, including adult glioblastoma (GBM), anaplastic oligodendroglioma, pediatric GBM, and diffuse intrinsic pontine glioma (DIPG) 1 . An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule neuroligin-3 (NLGN3), which promotes glioma proliferation through the PI3K-mTOR pathway 1 . However, neuroligin-3 necessity to glioma growth, proteolytic mechanism of secretion and further molecular consequences in glioma remain to be clarified.…”