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Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma

ABSTRACT: Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma

PROVIDER: PRJNA1160219 | ENA |

REPOSITORIES: ENA

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Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma [2]

Project description: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.

2024-10-30 | GSE277014 | GEO

Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma [1]

2024-10-30 | GSE277011 | GEO

Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma [2]

Project description:Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma [2]

| PRJNA1160224 | ENA

Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma [1]

Project description:Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma [1]

| PRJNA1160226 | ENA

Endothelial-secreted Endocan protein acts as a PDGFR alpha ligand and regulates vascularity, radioresistance, and regional phenotype in glioblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-10-30 | GSE277015 | GEO

Endocan-PDGFRα mediated signaling drives glioblastoma spatial heterogeneity and influences tumor vasculature/radioresistance

Project description:Endocan-PDGFRα mediated signaling drives glioblastoma spatial heterogeneity and influences tumor vasculature/radioresistance

| PRJNA573099 | ENA

Endocan-PDGFRα mediated signaling drives glioblastoma spatial heterogeneity and influences tumor vasculature/radioresistance [ATAC-seq]

Project description:Endocan-PDGFRα mediated signaling drives glioblastoma spatial heterogeneity and influences tumor vasculature/radioresistance [ATAC-seq]

| PRJNA573085 | ENA

Endocan-PDGFRα mediated signaling drives glioblastoma spatial heterogeneity and influences tumor vasculature/radioresistance [RNA-seq]

Project description:Endocan-PDGFRα mediated signaling drives glioblastoma spatial heterogeneity and influences tumor vasculature/radioresistance [RNA-seq]

| PRJNA573102 | ENA

Dysregulated mesenchymal PDGFR-β drives kidney fibrosis

Project description:Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-β (PDGFR-β) positive mesenchymal cells. To study the consequences of PDGFR-ß activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch towards myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. We used microarrays to compare wildtype animals (Foxd1_wt Pdgfrb_wt) to animals with constitutive mesenchymal PDGFR-β activation (Foxd1_mt Pdgfrb V536A) in the kidney to identify target genes of PDGFR-β signaling.

2019-12-06 | GSE138819 | GEO

Synectin Promotes Fibrogenesis by Regulating PDGFR Isoforms Through Distinct Mechanisms

Project description:The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As the platelet derived growth factor receptor (PDGFR) pathway is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway in HSC. To study the role of synectin in the development of liver fibrosis, mice with selective deletion of synectin from HSC were generated and found to be protected from fibrosis. RNAseq revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes including PDGFR-β, but not PDGFR-α. Chromatin Immunoprecipitation assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300. In contradistinction, synectin was found to regulate PDGFR-α through an alternative mechanism: protection from autophagic degradation. Site directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues is responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF dependent proliferation and migration after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin expression. This work provides insight into differential transcriptional and post-translational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.

2017-12-31 | GSE93629 | GEO

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