Heparan Sulfate Synthesized by Ext1 Regulates Receptor Tyrosine Kinase Signaling and Promotes Resistance to EGFR Inhibitors in GBM
| Autor: | Ohkawa, Yuki, Wade, Anna, Lindberg, Olle R, Chen, Katharine Y, Tran, Vy M, Brown, Spencer J, Kumar, Anupam, Kalita, Mausam, James, C David, Phillips, Joanna J |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Animal
Oncology and Carcinogenesis Neurosciences Receptor Protein-Tyrosine Kinases N-Acetylglucosaminyltransferases Brain Disorders ErbB Receptors Brain Cancer Mice Rare Diseases Disease Models Animals Humans 2.1 Biological and endogenous factors Heparitin Sulfate Oncology & Carcinogenesis Aetiology Glioblastoma Signal Transduction Cell Proliferation Cancer Developmental Biology |
| Zdroj: | Molecular cancer research : MCR, vol 19, iss 1 |
| Popis: | Signaling from multiple receptor tyrosine kinases (RTK) contributes to therapeutic resistance in glioblastoma (GBM). Heparan sulfate (HS), present on cell surfaces and in the extracellular matrix, regulates cell signaling via several mechanisms. To investigate the role for HS in promoting RTK signaling in GBM, we generated neural progenitor cells deficient for HS by knockout of the essential HS-biosynthetic enzyme Ext1, and studied tumor initiation and progression. HS-null cells had decreased proliferation, invasion, and reduced activation of multiple RTKs compared with control. In vivo tumor establishment was significantly decreased, and rate of tumor growth reduced with HS-deficient cells implanted in an HS-poor microenvironment. To investigate if HS regulates RTK activation through platelet-derived growth factor receptor α (PDGFRα) signaling, we removed cell surface HS in patient-derived GBM lines and identified reduced cell surface PDGF-BB ligand. Reduced ligand levels were associated with decreased phosphorylation of PDGFRα, suggesting HS promotes ligand-receptor interaction. Using human GBM tumorspheres and a murine GBM model, we show that ligand-mediated signaling can partially rescue cells from targeted RTK inhibition and that this effect is regulated by HS. Indeed, tumor cells deficient for HS had increased sensitivity to EGFR inhibition in vitro and in vivo. IMPLICATIONS: Our study shows that HS expressed on tumor cells and in the tumor microenvironment regulates ligand-mediated signaling, promoting tumor cell proliferation and invasion, and these factors contribute to decreased tumor cell response to targeted RTK inhibition. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|