Bastola Soniya, Pavlyukov Marat S, Sharma Neel, Ghochani Yasmin, Nakano Mayu A, Muthukrishnan Sree Deepthi, Yu Sang Yul, Kim Min Soo, Sohrabi Alireza, Biscola Natalia P, Yamashita Daisuke, Anufrieva Ksenia S, Kovalenko Tatyana F, Jung Grace, Ganz Tomas, O'Brien Beatrice, Kawaguchi Riki, Qin Yue, Seidlits Stephanie K, Burlingame Alma L, Oses-Prieto Juan A, Havton Leif A, Goldman Steven A, Hjelmeland Anita B, Nakano Ichiro, Kornblum Harley I
The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
Nat Commun. 2025 Jan 7;16(1):471. doi: 10.1038/s41467-024-55487-1.
Extensive neovascularization is a hallmark of glioblastoma (GBM). In addition to supplying oxygen and nutrients, vascular endothelial cells provide trophic support to GBM cells via paracrine signaling. Here we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing stable phenotypic changes in GBM cells. Furthermore, Endocan confers radioprotection on GBM cells in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue GBM recurrence and highlight the importance of vascular-tumor interactions for GBM development.
广泛的新血管生成是胶质母细胞瘤（GBM）的一个标志。除了提供氧气和营养物质外，血管内皮细胞还通过旁分泌信号为GBM细胞提供营养支持。在此，我们报告内皮细胞分泌的蛋白聚糖内皮糖蛋白（Endocan，ESM1）赋予GBM细胞增强的增殖、迁移和血管生成特性，并调节其空间特征。从机制上讲，Endocan至少部分通过直接结合和激活血小板衍生生长因子受体α（PDGFRA）发挥其功能。随后的下游信号增强了Myc启动子的染色质可及性，并上调Myc表达，诱导GBM细胞发生稳定的表型变化。此外，Endocan在体外和体内赋予GBM细胞放射保护作用。用波纳替尼抑制Endocan-PDGFRA信号通路可提高Esm1野生型小鼠GBM模型的生存率，但对Esm1基因敲除小鼠GBM模型无效。我们的研究结果确定Endocan及其下游信号轴是抑制GBM复发的潜在靶点，并突出了血管-肿瘤相互作用对GBM发展的重要性。
