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Tumor Microenvironment and Immunobiology

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 and Joanna J. Phillips
Yuki Ohkawa
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.
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Anna Wade
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.
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Olle R. Lindberg
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.
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  • ORCID record for Olle R. Lindberg
Katharine Y. Chen
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.
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Vy M. Tran
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.
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Spencer J. Brown
2Departments of Bioengineering and Medicinal Chemistry, University of Utah, Salt Lake City, Utah.
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Anupam Kumar
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.
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Mausam Kalita
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.
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C. David James
3Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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Joanna J. Phillips
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California.
4Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
5Division of Neuropathology, Department of Pathology, University of California, San Francisco, San Francisco, California.
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  • For correspondence: Joanna.phillips@ucsf.edu
DOI: 10.1158/1541-7786.MCR-20-0420 Published January 2021
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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 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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:150–61

  • Received May 6, 2020.
  • Revision received September 6, 2020.
  • Accepted October 1, 2020.
  • Published first October 7, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (1)
January 2021
Volume 19, Issue 1
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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 and Joanna J. Phillips
Mol Cancer Res January 1 2021 (19) (1) 150-161; DOI: 10.1158/1541-7786.MCR-20-0420

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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 and Joanna J. Phillips
Mol Cancer Res January 1 2021 (19) (1) 150-161; DOI: 10.1158/1541-7786.MCR-20-0420
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Molecular Cancer Research
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