小柯机器人

2021年5月26日，《自然》杂志在线发表了美国圣路易斯华盛顿大学David H. Gutmann、斯坦福大学Michelle Monje等研究人员的合作成果。该研究表明，NF1突变驱动视神经胶质瘤的神经元活动依赖性起始。

研究人员表示，神经元最近成为了肿瘤微环境中必不可少的细胞成分，其活性已显示出可促进多种实体瘤的生长。尽管以前已经证明了神经元在肿瘤进展中的作用，但神经元活性对肿瘤发生的重要性尚不清楚，尤其是在癌症易感综合症的发生中。患有神经纤维瘤病1（NF1）癌症易感综合征（其中的肿瘤与神经密切相关）的人中有15％在儿童早期就发展了低度的视神经瘤（称为视神经胶质瘤OPG），并且增加了产后光诱导的视神经活动驱动肿瘤发生的可能性。

研究人员使用由神经纤维瘤病1肿瘤抑制基因（Nf1）中突变驱动的OPG验证小鼠模型，来证明了刺激视神经活动会增加视神经胶质瘤的生长，并且通过光剥夺减少视觉体验会阻止肿瘤的形成和维持。结果表明，Nf1驱动的OPGs（Nf1-OPGs）起始取决于Nf1突变小鼠易发生肿瘤的发展时期的视觉体验。视网膜神经元中的生殖系Nf1突变导致视神经神经活动而引起的视神经内神经胶蛋白3（NLGN3）脱落异常增加。此外，遗传性Nlgn3丢失或NLGN3脱落的药理抑制作用会阻止Nf1-OPG的形成和发展。

总的来说，这项研究确立了神经元活动在某些类型的脑肿瘤的发展中的重要作用，阐明了降低OPG发生率或减轻肿瘤进展的治疗策略，并强调了Nf1突变介导的神经元信号通路失调在NF1癌症易感综合征小鼠模型中的作用 。

附：英文原文

Title: NF1 mutation drives neuronal activity-dependent initiation of optic glioma

Author: Yuan Pan, Jared D. Hysinger, Tara Barron, Nicki F. Schindler, Olivia Cobb, Xiaofan Guo, Belgin Yaln, 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

Issue&Volume: 2021-05-26

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.

DOI: 10.1038/s41586-021-03580-6

Source: https://www.nature.com/articles/s41586-021-03580-6

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