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

Soniya Bastola, Marat S. Pavlyukov, Neel Sharma, Yasmin Ghochani, Mayu A. Nakano, Sree Deepthi Muthukrishnan, Sang Yul Yu, Min Soo Kim, Alireza Sohrabi, Natalia P. Biscola, Daisuke Yamashita, Ksenia S. Anufrieva, Tatyana F. Kovalenko, Grace Jung, Tomas Ganz, Beatrice O’Brien, Riki Kawaguchi, Yue Qin, Stephanie K. Seidlits, Alma L. Burlingame, Juan A. Oses-Prieto, Leif A. Havton, Steven A. Goldman, Anita B. Hjelmeland, Ichiro Nakano () and Harley I. Kornblum ()
Additional contact information
Soniya Bastola: David Geffen School of Medicine at UCLA
Marat S. Pavlyukov: David Geffen School of Medicine at UCLA
Neel Sharma: David Geffen School of Medicine at UCLA
Yasmin Ghochani: David Geffen School of Medicine at UCLA
Mayu A. Nakano: University of Alabama at Birmingham
Sree Deepthi Muthukrishnan: David Geffen School of Medicine at UCLA
Sang Yul Yu: David Geffen School of Medicine at UCLA
Min Soo Kim: David Geffen School of Medicine at UCLA
Alireza Sohrabi: University of Texas at Austin
Natalia P. Biscola: Icahn School of Medicine at Mount Sinai
Daisuke Yamashita: Ehime University Graduate School of Medicine, Shitsukawa 454
Ksenia S. Anufrieva: Center for Precision Genome Editing and Genetic Technologies for Biomedicine of Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency
Tatyana F. Kovalenko: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry
Grace Jung: David Geffen School of Medicine at UCLA
Tomas Ganz: David Geffen School of Medicine at UCLA
Beatrice O’Brien: David Geffen School of Medicine at UCLA
Riki Kawaguchi: David Geffen School of Medicine at UCLA
Yue Qin: David Geffen School of Medicine at UCLA
Stephanie K. Seidlits: University of Texas at Austin
Alma L. Burlingame: University of California
Juan A. Oses-Prieto: University of California
Leif A. Havton: James J Peters VA Medical Center
Steven A. Goldman: University of Rochester Medical Center
Anita B. Hjelmeland: University of Alabama at Birmingham
Ichiro Nakano: Iruma
Harley I. Kornblum: David Geffen School of Medicine at UCLA

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-024-55487-1

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