Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.

Abstract

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.

• Authors: Humsa S Venkatesh, Tessa B Johung, Viola Caretti, Alyssa Noll, Yujie Tang, Surya Nagaraja, Erin M Gibson, Christopher W Mount, Jai Polepalli, Siddhartha S Mitra, Pamelyn J Woo, Robert C Malenka, Hannes Vogel, Markus Bredel, Parag Mallick, Michelle Monje
• Journal: Cell (Cell) Vol. 161 Issue 4 Pg. 803-16 (May 07 2015) ISSN: 1097-4172 [Electronic] United States
• PMID: 25913192 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Cell Adhesion Molecules, Neuronal
• Membrane Proteins
• Nerve Tissue Proteins
• neuroligin 3

Topics

• Adolescent
• Amino Acid Sequence
• Animals
• Brain Neoplasms (metabolism, pathology)
• Cell Adhesion Molecules, Neuronal (metabolism)
• Cell Proliferation
• Glioma (metabolism, pathology)
• Heterografts
• Humans
• Male
• Membrane Proteins (metabolism)
• Mice
• Molecular Sequence Data
• Neoplasm Transplantation
• Nerve Tissue Proteins (metabolism)
• Neurons (metabolism)