NF1 mutation drives neuronal activity-dependent initiation of optic glioma

Nature, published online: 26 May 2021

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 tumours. Although the role of neurons in tumour progression
has previously been demonstrated, 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 neurofbromatosis 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 childhood, 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 neurofbromatosis 1 tumour
suppressor gene (Nf1) to demo nstrate 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.

Yuan Pan, Jared D. Hysinger, Tara Barron, Nicki F. Schindler, Olivia Cobb, Xiaofan Guo,
Belgin Yalçın, Corina Anastasaki, Sara B. Mulinyawe, Anitha Ponnuswami, Suzanne Scheaffer, Yu Ma, Kun-Che Chang, Xin Xia, Joseph A. Toonen, James J. Lennon, Erin M. Gibson, John R. Huguenard, Linda M. Liau, Jeffrey L. Goldberg, Michelle Monje &
David H. Gutmann

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