Neuronal Regulation of Low-Grade Gliomagenesis

低度胶质瘤发生的神经元调节

• 批准号: 10596172
• 负责人: David H Gutmann
• 金额: $ 62.57万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596172
• 关键词: Accounting; Adult; Age; Attenuated; Biology; Brain; Brain Neoplasms; Cells; Cessation of life; Child; Childhood; Darkness; Data; Development; Diagnosis; Evolution; Exhibits; Foundations; Genetic; Glioma; Gliomagenesis; Goals; Growth; Growth Factor; Histologic; Human; In Vitro; Laboratories; Light; Maintenance; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Mutant Strains Mice; NF1 gene; NF1 mutation; Neurocognitive; Neurofibromatosis 1; Neurons; Optic Chiasm; Optic Nerve; Optic Nerve Glioma; Optics; Outcome; Pathogenesis; Pathway interactions; Patients; Pediatric Neoplasm; Penetrance; Primary Brain Neoplasms; Production; Proliferating; Regulation; Retina; Retinal Ganglion Cells; Role; Signal Induction; Signal Transduction; Syndrome; Transcriptional Regulation; Tumor Suppressor Proteins; Visual impairment; cancer predisposition; cancer type; early childhood; experimental study; genetic approach; improved; in vivo; inhibitor; light deprivation; light transmission; mouse model; mutant; neoplastic cell; neuroligin 3; neuronal excitability; neurotoxicity; neurotransmission; optogenetics; paracrine; pharmacologic; pre-clinical; prevent; response; retinal axon; retinal stimulation; tumor; tumor growth; tumor microenvironment; tumorigenesis

Project Summary Gliomas comprise the most common form of brain cancer. In adults and children, high-grade gliomas are the leading cause of brain cancer-related death, whereas the neurotoxicity associated with the treatment of pediatric low-grade gliomas (LGGs) frequently results in long-term neurocognitive sequelae. For these reasons, there is a pressing need to better define the mechanisms that underlie glioma development and progression relevant to improving treatment and reducing lifelong neurotoxicity. This is especially important for children with the Neurofibromatosis type 1 (NF1) cancer predisposition who develop low-grade optic pathway gliomas (OPGs) that impair vision. These NF1-OPGs form during early childhood (mean age, 4.5 years), where they are localized to the optic nerve and/or chiasm containing the axons of retinal ganglion cells (RGCs) - the neuronal subtype responsible for transmitting light-induced signals from the retina to the brain. Given the intimate relationship between these tumors and the optic nerve, a collaborative venture between the Monje and Gutmann laboratories resulted in the identification of a key regulatory role for neurons in NF1-OPG biology using authenticated preclinical Nf1 optic glioma mouse strains that histologically resemble their human counterparts. In these studies, we found that decreasing retinal ganglion cell (RGC) neuronal activity prior to tumor formation prevents OPG initiation, while reduced RGC neuronal activity attenuates established OPG growth. In addition, Nf1 mutant (similar to patients with NF1), but not wild-type (normal), optic nerves exhibit increased neuroligin-3 expression and secretion in response to RGC activity, which is controlled by ADAM10 cleavage. Moreover, neuroligin-3 (Nlgn3) is a potent growth factor for Nf1-deficient OPG cells in vitro and genetic loss of neuroligin-3 in Nf1 optic pathway glioma mice blocks tumor formation in vivo. Lastly, inhibition of neuroligin-3 shedding using ADAM10 inhibitors reduces Nf1-OPG growth. Based on these exciting preliminary data, we hypothesize that Nf1 mutation in RGC neurons promotes dysregulated neuroligin-3 signaling that drives the initiation and maintenance of Nf1 optic glioma. In this collaborative R01 proposal, we aim to elucidate the intersection between cell-intrinsic vulnerability (NF1 tumor suppressor loss) and paracrine influences from neurons in the tumor microenvironment relevant to understanding the pathogenesis of these common brain tumors in children with NF1.

项目摘要 胶质瘤是最常见的脑癌形式。在成人和儿童中，高级别胶质瘤是 脑癌相关死亡的主要原因，而与治疗儿童脑癌有关的神经毒性 低级别胶质瘤(LGG)经常导致长期的神经认知后遗症。出于这些原因，有 迫切需要更好地定义脑胶质瘤发生和发展的相关机制 改善治疗，减少终生神经毒性。这一点对于患有 神经纤维瘤病1型(NF1)患低级别视路胶质瘤(OPGs)的癌症易感性 这会损害视力。这些NF1-OPG形成于儿童早期(平均年龄4.5岁)，在那里他们是本地化的 视神经和/或包含视网膜神经节细胞(RGC)轴突的交叉--神经元亚型 负责将光诱导的信号从视网膜传输到大脑。鉴于这种亲密的关系 在这些肿瘤和视神经之间，Monje和Gutmann实验室之间的合作项目 结果确定了神经元在NF1-OPG生物学中的关键调节作用 临床前NF1视神经胶质瘤小鼠品系，在组织学上与其人类同龄人相似。在这些研究中， 我们发现，在肿瘤形成之前，减少视网膜神经节细胞(RGC)神经元的活动可以防止OPG 当RGC神经元活性降低时，已建立的OPG生长减弱。此外，NF1突变体 (与NF1患者相似)，但不是野生型(正常)，视神经表现出神经连接蛋白-3的表达增加 和分泌对RGC活性的反应，这是由ADAM10切割控制的。此外，神经连接蛋白-3 (Nlgn3)是NF1缺陷型OPG细胞的有效生长因子及NF1视神经细胞中NL3的遗传缺失 途径胶质瘤小鼠阻断体内肿瘤的形成。最后，使用ADAM10抑制神经连接蛋白-3的脱落 抑制剂会减少NF1-OPG的生长。基于这些令人兴奋的初步数据，我们假设NF1突变 在RGC中，神经元促进失调的神经连接蛋白-3信号，从而驱动NF1的启动和维持 视神经胶质瘤。在这个协作的R01提案中，我们的目标是阐明细胞-内在的交集 肿瘤微环境中神经元的脆弱性(NF1肿瘤抑制因子缺失)和旁分泌影响 这与了解NF1儿童常见脑肿瘤的发病机制有关。