Active Neurons Secrete Neuroligin 3 to Promote Glioma Proliferation

High-grade gliomas (HGG) are the leading cause of brain tumor death in children and adults, yet little is known about the microenvironmental influences that drive glioma growth. Neuronal activity in the juvenile and adult brain promotes the proliferation of normal neural and oligodendroglial precursor cells, which have been suggested to give rise to HGG. Venkatesh, Johung, Caretti, and colleagues examined the role of neuronal activity in promoting HGG proliferation using optogenetic stimulation of the premotor cortex in mice bearing patient-derived pediatric cortical glioblastoma xenografts. Activation of motor cortex projection neurons by exposure to light increased the proliferation index of human HGG cells and resulted in increased tumor burden specifically within the active circuit. In addition, conditioned medium from optogenetically stimulated acute cortical slices increased the proliferation of patient-derived HGG cells in vitro, demonstrating that neuronal activity induces tumor cell proliferation through secreted mitogens. A similar proliferative response to neuronal activity–regulated secreted factors was seen across different HGG subtypes, suggesting that neuronal mitogens function broadly to promote brain tumor growth. Biochemical analyses identified the synaptic protein neuroligin 3 (NLGN3) as the leading candidate neuronal activity–regulated mitogen. Recombinant NLGN3 elicited a similar increase in the proliferation of patient-derived HGG cells, whereas depletion of NLGN3 from conditioned medium decreased its mitogenic activity, indicating that NLGN3 is necessary and sufficient to promote glioma growth. Mechanistically, exposure to secreted NLGN3 upregulated PI3K–mTOR signaling in HGG cells, and blocking this pathway inhibited NLGN3-mediated proliferation. Secreted NLGN3 also positively regulated NLGN3 expression in glioma cells at the transcriptional and translational level via the PI3K–mTOR pathway. Importantly, although somatic mutations of NLGN3 were infrequent in pediatric and adult brain tumors, NLGN3 expression was inversely correlated with overall survival in glioblastoma. These studies reveal that excitatory neuronal activity in the tumor microenvironment promotes brain cancer growth.

Venkatesh HS, Johung TB, Caretti V, Noll A, Tang Y, Nagaraja S, et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 2015;161:803–16.

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