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.

项目概要 神经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，而与儿科治疗相关的神经毒性 低度恶性胶质瘤（LGG）经常导致长期的神经认知后遗症。由于这些原因，有 迫切需要更好地定义与神经胶质瘤发生和进展相关的机制 改善治疗并减少终生神经毒性。这对于患有以下疾病的儿童尤其重要 患有低级别视神经胶质瘤 (OPG) 的 1 型神经纤维瘤病 (NF1) 癌症倾向 从而损害视力。这些 NF1-OPG 在幼儿期（平均年龄 4.5 岁）形成，在那里它们局部化 包含视网膜神经节细胞 (RGC) 轴突的视神经和/或交叉 - 神经元亚型 负责将光感应信号从视网膜传输到大脑。鉴于亲密关系 Monje 和 Gutmann 实验室之间的合作项目，研究这些肿瘤和视神经之间的关系 结果使用经过验证的方法鉴定了 NF1-OPG 生物学中神经元的关键调节作用 临床前 Nf1 视神经胶质瘤小鼠品系在组织学上与人类对应品系相似。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) 神经元活动可以预防 OPG 启动，而 RGC 神经元活动的减少会减弱已建立的 OPG 生长。此外，Nf1突变体 （与 NF1 患者类似），但野生型（正常）视神经则表现出 Neuroligin-3 表达增加 以及响应 RGC 活动而分泌，这是由 ADAM10 裂解控制的。此外，neuroligin-3 (Nlgn3) 是一种有效的生长因子，适用于体外 Nf1 缺陷型 OPG 细胞以及 Nf1 视神经中 Neuroligin-3 的遗传缺失 神经胶质瘤小鼠体内阻断肿瘤形成。最后，使用 ADAM10 抑制 Neuroligin-3 脱落 抑制剂会降低 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 RGC 神经元中的神经胶质素 3 信号传导失调，从而驱动 Nf1 的启动和维持 视神经胶质瘤。在这个协作 R01 提案中，我们的目标是阐明细胞内在的交叉点 肿瘤微环境中神经元的脆弱性（NF1肿瘤抑制因子丧失）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。