Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma therapy. Homo sapiens

Neuronal activity promotes high-grade glioma (HGG) growth. An important mechanism mediating this neural regulation of brain cancer is activity-dependent cleavage and secretion of the synaptic molecule and glioma mitogen neuroligin-3 (Nlgn3), but the therapeutic potential of targeting Nlgn3 in glioma remains to be defined. We demonstrate a striking dependence of HGG growth on microenvironmental Nlgn3 and determine a targetable mechanism of secretion. Patient-derived orthotopic xenografts of pediatric glioblastoma, diffuse intrinsic pontine glioma and adult glioblastoma fail to grow in Nlgn3 knockout mice. Glioma exposure to Nlgn3 results in numerous signaling consequences, including early focal adhesion kinase activation upstream of PI3K-mTOR. Nlgn3 is cleaved from both neurons and oligodendrocyte precursor cells via the ADAM10 sheddase. Administration of ADAM10 inhibitors robustly blocks HGG xenograft growth. This work defines the therapeutic potential of and a promising strategy for targeting Nlgn3 secretion in the glioma microenvironment, which could prove transformative for treatment of HGG. Overall design: RNA-seq patient-derived pediatric GBM cell cultures in two replicates. Libraries were sequenced on Illumina NextSeq 500, 1x75.

神经元活动可促进高级别胶质瘤（high-grade glioma, HGG）的生长。介导该神经调控脑癌过程的重要机制，是突触分子兼胶质瘤有丝分裂原神经连接蛋白-3（Neuroligin-3, Nlgn3）的活性依赖性切割与分泌，但靶向Nlgn3用于胶质瘤治疗的潜力仍有待明确。
本研究证实了高级别胶质瘤生长对微环境中Nlgn3的显著依赖性，并明确了其可靶向的分泌调控机制。源自患者的儿童胶质母细胞瘤（pediatric glioblastoma）、弥漫内生型桥脑胶质瘤（diffuse intrinsic pontine glioma）以及成人胶质母细胞瘤（adult glioblastoma）的原位异种移植瘤（orthotopic xenografts），在Nlgn3基因敲除小鼠（knockout mice）中无法生长。
胶质瘤暴露于Nlgn3后会引发多种信号通路改变，包括磷脂酰肌醇3-激酶-哺乳动物雷帕霉素靶蛋白（PI3K-mTOR）通路上游的早期黏着斑激酶（focal adhesion kinase）激活。神经元与少突胶质前体细胞（oligodendrocyte precursor cells）均可通过ADAM10脱落酶（ADAM10）切割Nlgn3。施用ADAM10抑制剂可有效阻断高级别胶质瘤异种移植瘤的生长。
本研究明确了靶向胶质瘤微环境中Nlgn3分泌的治疗潜力与可行策略，有望为高级别胶质瘤的临床治疗带来革命性突破。
实验整体设计：对源自患者的儿童胶质母细胞瘤细胞培养物进行RNA测序，设置两个生物学重复。测序文库在Illumina NextSeq 500平台上以1×75的读长完成测序。