Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion

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 th...

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Bibliographic Details
Published in:	Cell 2015-05, Vol.161 (4), p.803-816
Main Authors:	Venkatesh, Humsa S., Johung, Tessa B., Caretti, Viola, Noll, Alyssa, Tang, Yujie, Nagaraja, Surya, Gibson, Erin M., Mount, Christopher W., Polepalli, Jai, Mitra, Siddhartha S., Woo, Pamelyn J., Malenka, Robert C., Vogel, Hannes, Bredel, Markus, Mallick, Parag, Monje, Michelle
Format:	Article
Language:	eng
Subjects:	Adolescent Amino Acid Sequence Animals Brain Neoplasms - metabolism Brain Neoplasms - pathology Cell Adhesion Molecules, Neuronal - metabolism Cell Proliferation Glioma - metabolism Glioma - pathology Heterografts Humans Male Membrane Proteins - metabolism Mice Molecular Sequence Data Neoplasm Transplantation Nerve Tissue Proteins - metabolism Neurons - metabolism
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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. [Display omitted] •Neuronal activity promotes high-grade glioma (HGG) proliferation and growth•Neuroligin-3 is an activity-regulated secreted glioma mitogen•Neuroligin-3 induces PI3K-mTOR signaling in HGG cells•Neuroligin-3 expression is inversely correlated with survival in human HGG Neuronal activity promotes the growth of malignant glioma through activity-regulated secretion of the synaptic protein neuroligin-3, which acts as a mitogen, recruiting the PI3K-mTOR pathway to induce glioma cell proliferation.
ISSN:	0092-8674 1097-4172