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; Harley I. Kornblum

doi:10.1038/s41467-024-55487-1

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. BurlingameJuan A. Oses-Prieto, Leif A. Havton, Steven A. Goldman, Anita B. Hjelmeland, Ichiro Nakano, Harley I. Kornblum^*

^*Corresponding author for this work

Center for Translational Neuromedicine

Research output: Contribution to journal › Journal article › Research › peer-review

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.

Original language	English
Article number	471
Journal	Nature Communications
Volume	16
Issue number	1
Number of pages	20
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-024-55487-1
Publication status	Published - 2025

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Publisher Copyright:
© The Author(s) 2025.

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Bastola, S., Pavlyukov, M. S., Sharma, N., Ghochani, Y., Nakano, M. A., Muthukrishnan, S. D., Yu, S. Y., Kim, M. S., Sohrabi, A., Biscola, N. P., Yamashita, D., Anufrieva, K. S., Kovalenko, T. F., Jung, G., Ganz, T., O’Brien, B., Kawaguchi, R., Qin, Y., Seidlits, S. K., ... Kornblum, H. I. (2025). Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma. Nature Communications, 16(1), [471]. https://doi.org/10.1038/s41467-024-55487-1

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

In: Nature Communications, Vol. 16, No. 1, 471, 2025.

Research output: Contribution to journal › Journal article › Research › peer-review

Bastola, S, Pavlyukov, MS, Sharma, N, Ghochani, Y, Nakano, MA, Muthukrishnan, SD, Yu, SY, Kim, MS, Sohrabi, A, Biscola, NP, Yamashita, D, Anufrieva, KS, Kovalenko, TF, Jung, G, Ganz, T, O’Brien, B, Kawaguchi, R, Qin, Y, Seidlits, SK, Burlingame, AL, Oses-Prieto, JA, Havton, LA, Goldman, SA, Hjelmeland, AB, Nakano, I & Kornblum, HI 2025, 'Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma', Nature Communications, vol. 16, no. 1, 471. https://doi.org/10.1038/s41467-024-55487-1

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. / Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma. In: Nature Communications. 2025 ; Vol. 16, No. 1.

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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.",

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AU - Bastola, Soniya

AU - Pavlyukov, Marat S.

AU - Sharma, Neel

AU - Ghochani, Yasmin

AU - Nakano, Mayu A.

AU - Muthukrishnan, Sree Deepthi

AU - Yu, Sang Yul

AU - Kim, Min Soo

AU - Sohrabi, Alireza

AU - Biscola, Natalia P.

AU - Yamashita, Daisuke

AU - Anufrieva, Ksenia S.

AU - Kovalenko, Tatyana F.

AU - Jung, Grace

AU - Ganz, Tomas

AU - O’Brien, Beatrice

AU - Kawaguchi, Riki

AU - Qin, Yue

AU - Seidlits, Stephanie K.

AU - Burlingame, Alma L.

AU - Oses-Prieto, Juan A.

AU - Havton, Leif A.

AU - Goldman, Steven A.

AU - Hjelmeland, Anita B.

AU - Nakano, Ichiro

AU - Kornblum, Harley I.

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N2 - 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.

AB - 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.

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