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

Author

Listed:
  • Soniya Bastola

    (David Geffen School of Medicine at UCLA)

  • Marat S. Pavlyukov

    (David Geffen School of Medicine at UCLA
    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry)

  • 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
    Johns Hopkins University School of Medicine)

  • 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
    Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and 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
    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
    University of Copenhagen)

  • Anita B. Hjelmeland

    (University of Alabama at Birmingham)

  • Ichiro Nakano

    (Iruma)

  • Harley I. Kornblum

    (David Geffen School of Medicine at UCLA)

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.

Suggested Citation

  • 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, 2025. "Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55487-1
    DOI: 10.1038/s41467-024-55487-1
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    References listed on IDEAS

    as
    1. Soniya Bastola & Marat S. Pavlyukov & Daisuke Yamashita & Sadashib Ghosh & Heejin Cho & Noritaka Kagaya & Zhuo Zhang & Mutsuko Minata & Yeri Lee & Hirokazu Sadahiro & Shinobu Yamaguchi & Svetlana Koma, 2020. "Glioma-initiating cells at tumor edge gain signals from tumor core cells to promote their malignancy," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    2. Sree Deepthi Muthukrishnan & Riki Kawaguchi & Pooja Nair & Rachna Prasad & Yue Qin & Maverick Johnson & Qing Wang & Nathan VanderVeer-Harris & Amy Pham & Alvaro G. Alvarado & Michael C. Condro & Fuyin, 2022. "P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
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