@article{7f11c61e58204cd8a80284f86a7858c9,
title = "NF1 mutation drives neuronal activity-dependent initiation of optic glioma",
abstract = "Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear—particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.",
author = "Yuan Pan and Hysinger, {Jared D.} and Tara Barron and Schindler, {Nicki F.} and Olivia Cobb and Xiaofan Guo and Belgin Yal{\c c}ın and Corina Anastasaki and Mulinyawe, {Sara B.} and Anitha Ponnuswami and Suzanne Scheaffer and Yu Ma and Chang, {Kun Che} and Xin Xia and Toonen, {Joseph A.} and Lennon, {James J.} and Gibson, {Erin M.} and Huguenard, {John R.} and Liau, {Linda M.} and Goldberg, {Jeffrey L.} and Michelle Monje and Gutmann, {David H.}",
note = "Funding Information: Acknowledgements This work was supported by grants from the Department of Defense (W81XWH-15-1-0131 to M.M. and D.H.G., and W81XWH-19-1-0260 to Y.P.), National Institute of Neurological Disorders and Stroke (R01NS092597 to M.M. and R35NS07211 to D.H.G.), NIH Director{\textquoteright}s Pioneer Award (DP1NS111132 to M.M.), National Cancer Institute (P50CA165962), National Eye Institute (P30EY026877 to J.L.G. and F32EY029137 to K.-C.C.), Brantley{\textquoteright}s Project supported by Ian{\textquoteright}s Friends Foundation (to Y.P. and M.M.), Gilbert Family Foundation (to D.H.G. and J.L.G.), Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (to M.M.), Cancer Research UK (to M.M.), Unravel Pediatric Cancer (to M.M.), McKenna Claire Foundation (to M.M.), Kyle O{\textquoteright}Connell Foundation (to M.M.), Virginia and D. K. Ludwig Fund for Cancer Research (to M.M.), Waxman Family Research Fund (to M.M.), Stanford Maternal and Child Health Research Institute (to E.M.G.), Stanford Bio-X Institute (to J.D.H.), Will Irwin Research Fund (to M.M.), Research to Prevent Blindness, Inc. (to J.L.G.) and Alex{\textquoteright}s Lemonade Stand Foundation (to Y.P.) The authors thank G. Grant and A. Bet for low-grade glioma samples from the Stanford Center for Childhood Brain Tumors Tissue Bank; C. Gardner from The St. Louis Children{\textquoteright}s Hospital Pediatric Tumor Bank (supported by the St. Louis Children{\textquoteright}s Hospital Foundation and Children{\textquoteright}s Surgical Sciences Institute); and Stanford Animal Histology Services for optic nerve paraffin-block sectioning. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = jun,
day = "10",
doi = "10.1038/s41586-021-03580-6",
language = "English",
volume = "594",
pages = "277--282",
journal = "Nature",
issn = "0028-0836",
number = "7862",
}