Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma

• Published in: Nature communications 2025-01, Vol.16 (1), p.471, Article 471
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/100; 13/106; 13/109; 13/89; 13/95; 38; 38/22; 38/91; 45/23; 45/77; 631/67/1922; 631/67/327; 82/103; 82/58; Angiogenesis; Animals; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell activation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell survival; Chromatin; Endothelial cells; Endothelial Cells - metabolism; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioma; Humanities and Social Sciences; Humans; Mice; Mice, Knockout; multidisciplinary; Myc protein; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Nutrients; Paracrine signalling; Phenotype; Phenotypes; Proteoglycans; Proteoglycans - genetics; Proteoglycans - metabolism; Radiation protection; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Receptors; Science; Science (multidisciplinary); Signal Transduction; Tumors; Vascularization
• ISSN: 2041-1723; 2041-1723
• 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. Glioblastoma (GBM) is rich in tumor-associated vasculature and it remains to be understood how GBM is supported by vascular endothelial cells. Here, the authors identify that endothelial-secreted proteoglycan endocan acts as a ligand of PDGFR alpha receptor to promote GBM progression and induce therapy resistance.