Min Peng-Xiang, Feng Li-Li, Zhang Yi-Xuan, Jiang Chen-Chen, Zhang Hong-Zhen, Chen Yan, Fukunaga Kohji, Liu Fang, Zhang Yu-Jie, Sasaki Takuya, Qian Xu, Horimoto Katsuhisa, Jiang Jian-Dong, Lu Ying-Mei, Han Feng
Key Laboratory of Modern Toxicology of Ministry of Education; School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
Cell Death Differ. 2025 Jun 18. doi: 10.1038/s41418-025-01534-3.
The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients.
胶质母细胞瘤（GBM）患者预后较差，主要归因于丰富的新生血管形成和胶质母细胞瘤干细胞（GSCs）的存在。GSCs优先定位于血管周围微环境以维持干性。然而，内皮细胞（ECs）与GSCs之间异常通讯对GBM进展的影响仍不清楚。在此，我们发现GBM患者中异常表达的ECs来源的SEMA3G通过诱导c-Myc降解来损害GSCs。SEMA3G以旁分泌方式激活NRP2/PLXNA1，随后诱导GSCs中Cdc42失活以及Cdc42与WWP2解离。一旦释放，WWP2与c-Myc相互作用并通过泛素化介导c-Myc降解。ECs中Sema3G的基因缺失会加速GBM生长，而SEMA3G过表达或重组SEMA3G蛋白可延长荷GBM小鼠的生存期。这些发现表明，ECs通过SMEA3G-c-Myc远端调控模式对GSCs干性发挥内在抑制作用。靶向SEMA3G信号通路可能对GBM患者具有有前景的治疗益处。
