Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma
Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma
Abstract One of the hallmarks of glioblastoma (GBM) is extensive neovascularization. In addition to supplying blood and nutrients, vascular endothelial (VE) cells provide trophic support to GBM cells via paracrine signaling, the precise mechanisms of which are being unraveled. Here, using patient-derived GBM and VE cells as well as orthotopic GBM mouse models, 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 highly stable phenotypic changes in GBM cells. Furthermore, Endocan confers a radioprotection phenotype in GBM cells, both 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 the recurrence of GBM and further highlight the importance of vascular to tumor cell signaling for GBM biology. Significance statementIdentification of the Endocan/PDGFRA/Myc axis demonstrates an important role of VE cells in GBM malignancy. The contribution of Endocan to the development of GBM cell populations with different phenotypes reveal an additional pathway underlying the origin of GBM intratumoral heterogeneity. Targeting Endocan-mediated crosstalk may enhance the efficacy of GBM treatment.
Kornblum Harley I.、Havton Leif A.、Hjelmeland Anita B.、Bastola Soniya、Ghochani Yasmin、Sohrabi Alireza、Biscola Natalia P.、Anufrieva Ksenia S.、Kim Min Soo、Kawaguchi Riki、Sharma Neel、Nakano Mayu A.、Yamashita Daisuke、Pavlyukov Marat S.、Nakano Ichiro、Qin Yue、Oses-Prieto Juan A.、Muthukrishnan Sree Deepthi、Goldman Steven A.、Burlingame Alma L、Yu Sang Yul、Seidlits Stephanie K.
The 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 UCLADepartments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai James J Peters VA Medical CenterDepartment of Cell, Developmental and Integrative Biology, 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 UCLA||Department of Bioengineering, University of California Los AngelesThe 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 California Los AngelesDepartment of Neurology, Icahn School of Medicine at Mount SinaiCenter for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency Moscow Institute of Physics and TechnologyThe 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 UCLA||Johns Hopkins University School of MedicineInterdepartmental Program in Bioinformatics, Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLA, Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Neurology, David Geffen School of Medicine, University of CaliforniaThe 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 BirminghamDepartment of Neurosurgery, Ehime University Graduate School of MedicineThe 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 Neurosurgery, Harada Hospital Address: 1-13-3 ToyookaInterdepartmental Program in Bioinformatics, Program in Neurogenetics, Department of Neurology and Department of Human Genetics, David Geffen School of Medicine at UCLA, Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Neurology, David Geffen School of Medicine, University of CaliforniaDepartment of Pharmaceutical Chemistry, University of CaliforniaThe 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 UCLACenter for Translational Neuromedicine, University of Rochester Medical Center Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Pharmaceutical Chemistry, University of CaliforniaThe 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 California Los Angeles
肿瘤学神经病学、精神病学基础医学
brain cancergliomaglioblastomaEndocanEsm1PDGFRAMycangiogenesisendothelial cellsradioresistance
Kornblum Harley I.,Havton Leif A.,Hjelmeland Anita B.,Bastola Soniya,Ghochani Yasmin,Sohrabi Alireza,Biscola Natalia P.,Anufrieva Ksenia S.,Kim Min Soo,Kawaguchi Riki,Sharma Neel,Nakano Mayu A.,Yamashita Daisuke,Pavlyukov Marat S.,Nakano Ichiro,Qin Yue,Oses-Prieto Juan A.,Muthukrishnan Sree Deepthi,Goldman Steven A.,Burlingame Alma L,Yu Sang Yul,Seidlits Stephanie K..Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2020.10.12.335091.点此复制
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