Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma
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 enhance...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55487-1 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Soniya Bastola |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d8fd1a3efd004fff842afb85e40eeafe |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d8fd1a3efd004fff842afb85e40eeafe2025-01-12T12:31:19ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-024-55487-1Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastomaSoniya Bastola0Marat S. Pavlyukov1Neel Sharma2Yasmin Ghochani3Mayu A. Nakano4Sree Deepthi Muthukrishnan5Sang Yul Yu6Min Soo Kim7Alireza Sohrabi8Natalia P. Biscola9Daisuke Yamashita10Ksenia S. Anufrieva11Tatyana F. Kovalenko12Grace Jung13Tomas Ganz14Beatrice O’Brien15Riki Kawaguchi16Yue Qin17Stephanie K. Seidlits18Alma L. Burlingame19Juan A. Oses-Prieto20Leif A. Havton21Steven A. Goldman22Anita B. Hjelmeland23Ichiro Nakano24Harley I. Kornblum25The Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAPrecision Medicine Institute, University of Alabama at BirminghamThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLADepartment of Bioengineering, University of Texas at AustinDepartment of Neurology, Icahn School of Medicine at Mount SinaiDepartment of Neurosurgery, Ehime University Graduate School of Medicine, Shitsukawa 454Center for Precision Genome Editing and Genetic Technologies for Biomedicine of Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological AgencyShemyakin-Ovchinnikov Institute of Bioorganic ChemistryDepartment of Medicine, Center for Iron Disorders, David Geffen School of Medicine at UCLADepartment of Medicine, Center for Iron Disorders, David Geffen School of Medicine at UCLAThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAInterdepartmental Program in Bioinformatics, Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLADepartment of Bioengineering, University of Texas at AustinDepartment of Pharmaceutical Chemistry, University of CaliforniaDepartment of Pharmaceutical Chemistry, University of CaliforniaDepartments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, James J Peters VA Medical CenterCenter for Translational Neuromedicine, University of Rochester Medical CenterDepartment of Cell, Developmental and Integrative Biology, University of Alabama at BirminghamDepartment of Neurosurgery, Harada Hospital, IrumaThe Intellectual and Developmental Disabilities Research Center, The Semel Institute for Neuroscience and Human Behavior, and The Broad Stem Cell Research Center, The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLAAbstract 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.https://doi.org/10.1038/s41467-024-55487-1 |
| spellingShingle | 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 Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma Nature Communications |
| title | Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma |
| title_full | Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma |
| title_fullStr | Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma |
| title_full_unstemmed | Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma |
| title_short | Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma |
| title_sort | endothelial secreted endocan activates pdgfra and regulates vascularity and spatial phenotype in glioblastoma |
| url | https://doi.org/10.1038/s41467-024-55487-1 |
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