Heparan sulfate synthesized by ext1 regulates receptor tyrosine kinase signaling and promotes resistance to EGFR inhibitors in GBM

Yuki Ohkawa, Anna Wade, Olle R. Lindberg, Katharine Y. Chen, Vy M. Tran, Spencer J. Brown, Anupam Kumar, Mausam Kalita, C. David James, Joanna J. Phillips*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 a (PDGFRa) 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 PDGFRa, 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.

Original languageEnglish (US)
Pages (from-to)150-160
Number of pages11
JournalMolecular Cancer Research
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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