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 childhood^3,4, 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.

神经元最近已成为肿瘤微环境的重要细胞成分，其活性已被证明可促进多种实体瘤的生长¹。尽管神经元在肿瘤进展中的作用先前已得到证实²，但神经元活动对肿瘤发生的重要性尚不清楚 - 特别是在癌症易感综合征的情况下。15% 患有神经纤维瘤病 1 (NF1) 癌症易感综合征（肿瘤与神经密切相关）的个体在儿童早期发展为视神经通路的低级别肿瘤（称为视神经通路神经胶质瘤 (OPG)）3 ^{， 4个}，提高了视神经的出生后光诱导活动驱动肿瘤发生的可能性。在这里，我们使用经过验证的 OPG 小鼠模型，该模型由神经纤维瘤病 1 肿瘤抑制基因 ( Nf1 ) ⁵中的突变驱动，以证明刺激视神经活动会增加视神经胶质瘤的生长，并且通过剥夺光线减少视觉体验可防止肿瘤形成和维持。我们表明， Nf1驱动的 OPGs ( Nf1- OPGs)的启动取决于Nf1突变小鼠易患肿瘤发生的发育时期的视觉体验。种系Nf1视网膜神经元的突变导致视神经内 neuroligin 3 (NLGN3) 的脱落异常增加，以响应视网膜神经元活动。此外，遗传性Nlgn3缺失或 NLGN3 脱落的药理学抑制可阻断Nf1- OPG的形成和进展。总的来说，我们的研究确定了神经元活动在某些类型脑肿瘤发展中的必要作用，阐明了降低 OPG 发生率或减缓肿瘤进展的治疗策略，并强调了Nf1突变介导的小鼠神经元信号通路失调的作用NF1 癌症易感综合征模型。