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NF1 mutation drives neuronal activity-dependent initiation of optic glioma

机译：NF1突变驱动视神经胶质瘤的神经元活性依赖性启动

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摘要

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~(1). Although the role of neurons in tumour progression has previously been demonstrated~(2), 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.
机译：神经元最近被出现为肿瘤微环境的基本细胞成分，并且其活性已被证明可以增加多种固体瘤的生长〜（1）。尽管神经元在肿瘤进展中的作用先前已经证明〜（2），但神经元活性对肿瘤起始的重要性较小 - 特别是在癌症预感综合征的环境中。具有神经纤维瘤病的十五％（NF1）癌症预感综合征（其中肿瘤与神经密切相关）在儿童早期开发光学途径的低级肿瘤（称为光学途径（OPGS））〜（ 3,4），提高后期光神经驱动肿瘤引发的产后光诱导活性的可能性。在这里，我们使用神经纤维瘤病中的突变驱动的官方验证的鼠标模型1肿瘤抑制基因（NF1）〜（5）证明视神经活性的刺激增加了视神经胶质瘤生长，并且通过剥夺剥夺降低视觉体验可防止肿瘤形成和维护。我们表明，NF1驱动的OPG（NF1-OPG）的开始取决于在发育期间的视觉体验，其中NF1-突变小鼠易受肿瘤发生的影响。视网膜神经元中的种系NF1突变导致视觉神经内的神经源素3（NLGN3）的异常增加，响应于视网膜神经元活性。此外，NLGN3脱落的遗传NLGN3损失或药理学抑制阻断NF1-OPG的形成和进展。集体，我们的研究建立了神经元活动在发育某些类型的脑肿瘤中的义务作用，阐明了治疗策略，以降低OPG发病率或减轻肿瘤进展，并强调NF1的作用介导的小鼠模型中神经元信号传导途径的作用NF1癌症预感综合征。

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  • 来源
    《Nature》 |2021年第7862期|277-282|共6页
  • 作者

    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;

  • 作者单位

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurology Washington University School of Medicine;

    Department of Neurology Washington University School of Medicine;

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurology Washington University School of Medicine;

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurology Washington University School of Medicine;

    Department of Neurology Washington University School of Medicine;

    Spencer Center for Vision Research Byers Eye Institute Stanford University;

    Spencer Center for Vision Research Byers Eye Institute Stanford University;

    Department of Neurology Washington University School of Medicine;

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurology and Neurological Sciences Stanford University|Department of Psychiatry and Behavioral Sciences Stanford University;

    Department of Neurology and Neurological Sciences Stanford University;

    Department of Neurosurgery University of California Los Angeles;

    Spencer Center for Vision Research Byers Eye Institute Stanford University;

    Department of Neurology and Neurological Sciences Stanford University|Department of Psychiatry and Behavioral Sciences Stanford University|Department of Pediatrics Stanford University|Department of Neurosurgery Stanford University|Department of Pathology Stanford University;

    Department of Neurology Washington University School of Medicine;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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