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A Mechanistic Understanding of Neuronal Activity Promotion of High-Grade Glioma Growth through Activity-Regulated Secretion of Neuroligin-3

通过活性调节的 Neuroligin-3 分泌促进高级别胶质瘤生长的神经元活性的机制理解

基本信息

批准号：
9333286
负责人：
Humsa Venkatesh
金额：
$ 3.81万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2018-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Microenvironmental determinants of glioma cell behavior are incompletely understood. The age and neuroanatomical location predilections of glioma occurrence indicate important interactions between the cell of origin and its microenvironment and suggest dysregulation of mechanisms of neurodevelopment and/or plasticity. We recently showed active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins for high-grade glioma (HGG). We now preliminarily demonstrate that active neurons similarly promote HGG proliferation in vivo using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma orthotopic xenograft model. Activity-regulated mitogen(s) are secreted, as the conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures. The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen; soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K pathway activity and feed-forward expression of NLGN3 in glioma cells, providing mechanistic insight into its surprising role as a mitogen. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted neuroligin-3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth. The proposed work aims to investigate further the direct interaction between NLNG3 and high-grade glioma cells. We will directly probe the necessity of NLGN3 in neuronal activity regulated glioma growth in an in vivo optogenetic model. Further, the research will identify mechanisms of secretion, receptor binding, and downstream signaling pathways. The proposed work highlights the previously under-recognized importance of neuronal activity in the glioma microenvironment, will result in a better mechanistic understanding of the newly identified glioma mitogen NLGN3, and may identify novel therapeutic targets to better treat these deadly brain tumors.

描述（由申请人提供）：神经胶质瘤细胞行为的微环境决定因素尚未完全了解。胶质瘤发生的年龄和神经解剖位置偏好表明起源细胞与其微环境之间的重要相互作用，并提示神经发育和/或可塑性机制的失调。我们最近发现活跃的神经元对正常的神经前体细胞和少突胶质前体细胞有促有丝分裂作用，这些细胞是高级别胶质瘤的假定细胞来源（HGG）。我们现在初步证明，活性神经元在体内同样促进HGG增殖，在患者来源的小儿胶质母细胞瘤原位异种移植模型中使用皮质神经元活性的光遗传学控制。分泌活性调节的有丝分裂原，因为来自光遗传学刺激的皮质切片的条件培养基促进儿科和成人患者来源的HGG培养物的增殖。突触蛋白神经连接素-3（NLGN 3）被鉴定为主要的候选有丝分裂原;可溶性NLGN 3是促进HGG细胞增殖的充分和必要条件。NLGN 3在神经胶质瘤细胞中诱导PI 3 K通路活性和NLGN 3的前馈表达，提供了对其作为有丝分裂原的惊人作用的机制见解。人HGG中的NLGN 3表达水平与患者总生存期呈负相关。这些发现表明活跃神经元在脑肿瘤微环境中的重要作用，并将分泌的神经配素-3鉴定为促进神经元活性调节的癌症生长的意想不到的机制。这项工作旨在进一步研究NLNG 3与高级别胶质瘤细胞之间的直接相互作用。我们将在体内光遗传学模型中直接探测NLGN 3在神经元活性调节胶质瘤生长中的必要性。此外，研究将确定分泌，受体结合和下游信号通路的机制。拟议的工作突出了神经胶质瘤微环境中神经元活动的重要性，将导致对新发现的神经胶质瘤有丝分裂原NLGN 3的更好的机制理解，并可能确定新的治疗靶点以更好地治疗这些致命的脑肿瘤。