One of the hallmarks of glioblastoma (GBM) is extensive neovascularization. In addition to supplying blood and nutrients, vascular endothelial (VE) cells provide trophic support to GBM cells via paracrine signaling, the precise mechanisms of which are being unraveled. Here, using patient-derived GBM and VE cells as well as orthotopic GBM mouse models, 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 highly stable phenotypic changes in GBM cells. Furthermore, Endocan confers a radioprotection phenotype in GBM cells, both 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 the recurrence of GBM and further highlight the importance of vascular to tumor cell signaling for GBM biology.

中文翻译：

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内皮分泌的 Endocan 蛋白充当 PDGFR α 配体并调节胶质母细胞瘤中的血管分布、放射抗性和区域表型

胶质母细胞瘤（GBM）的标志之一是广泛的新生血管形成。除了供应血液和营养物质外，血管内皮（VE）细胞还通过旁分泌信号为 GBM 细胞提供营养支持，其精确机制正在被阐明。在这里，使用患者来源的 GBM 和 VE 细胞以及原位 GBM 小鼠模型，我们报告了 Endocan (ESM1)，一种内皮分泌的蛋白多糖，赋予 GBM 细胞增强的增殖、迁移和血管生成特性，并调节它们的空间特性。从机制上讲，Endocan 至少通过直接结合和激活 PDGFRA 受体来发挥其部分功能。随后的下游信号传导增强了 Myc 启动子的染色质可及性并上调 Myc 表达，从而诱导 GBM 细胞中高度稳定的表型变化。此外，Endocan 在体外和体内赋予 GBM 细胞放射防护表型。用 ponatinib 抑制 Endocan-PDGFRA 信号传导可提高 Esm1 野生型的存活率，但不会提高 Esm1 敲除小鼠 GBM 模型的存活率。我们的研究结果将 Endocan 及其下游信号传导轴确定为抑制 GBM 复发的潜在靶标，并进一步强调了血管与肿瘤细胞信号传导对于 GBM 生物学的重要性。