Journal
CELL
Volume 161, Issue 4, Pages 803-816Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.04.012
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Funding
- Matthew Larson Foundation
- Godfrey Family Fund in Memory of Fiona Penelope
- National Institute of Neurological Disorders and Stroke (NINDS) [K08NS070926]
- McKenna Claire Foundation
- National Science Foundation Graduate Research Fellowship Program
- California Institute for Regenerative Medicine [CIRM RB4-06093, RN3-06510]
- Alex's Lemonade Stand Foundation
- Cure Starts Now Foundation
- Lyla Nsouli Foundation
- Unravel Pediatric Cancer
- Wayland Villars DIPG Foundation
- Jennifer Kranz Memorial Fund, virginia
- D.K. Ludwig Fund for Cancer Research
- Bear Necessities Pediatric Cancer Foundation
- Lucile Packard Foundation for Children's Health
- Stanford University School of Medicine Dean's Fellowship
- Child Health Research Institute at Stanford Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases
- National Cancer Institute [PSOC-MCSTART U54CA143907]
- Canary Foundation
- Ben and Catherine Ivy Foundation
- Sujal and Meera Patel Foundation
- Dylan Jewett Memorial Fund, Virginia
- Connor Johnson Memorial Fund, Virginia
- Zoey Ganesh Memorial Fund, Virginia
- Dylan Frick Memorial Fund, Virginia
- Abigail Jensen Memorial Fund, Virginia
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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 opto-genetically 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.
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