Hyaluronic acid fuels pancreatic cancer cell growth

  1. Peter K Kim
  2. Christopher J Halbrook
  3. Samuel A Kerk
  4. Megan Radyk
  5. Stephanie Wisner
  6. Daniel M Kremer
  7. Peter Sajjakulnukit
  8. Anthony Andren
  9. Sean W Hou
  10. Ayush Trivedi
  11. Galloway Thurston
  12. Abhinav Anand
  13. Liang Yan
  14. Lucia Salamanca-Cardona
  15. Samuel D Welling
  16. Li Zhang
  17. Matthew R Pratt
  18. Kayvan R Keshari
  19. Haoqiang Ying
  20. Costas Lyssiotis  Is a corresponding author
  1. University of Michigan, United States
  2. The University of Texas MD Anderson Cancer Center, United States
  3. Memorial Sloan Kettering Cancer Center, United States
  4. University of Southern California, United States

Abstract

Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; raw images have been provided for all western blots in the Source Data file.

Article and author information

Author details

  1. Peter K Kim

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9382-7223
  2. Christopher J Halbrook

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  3. Samuel A Kerk

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  4. Megan Radyk

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  5. Stephanie Wisner

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  6. Daniel M Kremer

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  7. Peter Sajjakulnukit

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  8. Anthony Andren

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  9. Sean W Hou

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  10. Ayush Trivedi

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  11. Galloway Thurston

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  12. Abhinav Anand

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  13. Liang Yan

    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    No competing interests declared.
  14. Lucia Salamanca-Cardona

    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, United States
    Competing interests
    No competing interests declared.
  15. Samuel D Welling

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  16. Li Zhang

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  17. Matthew R Pratt

    Department of Chemistry, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3205-5615
  18. Kayvan R Keshari

    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  19. Haoqiang Ying

    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    No competing interests declared.
  20. Costas Lyssiotis

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    For correspondence
    clyssiot@med.umich.edu
    Competing interests
    Costas Lyssiotis, has received consulting fees from Astellas Pharmaceuticals and Odyssey Therapeutics and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9309-6141

Funding

National Cancer Institute (Cancer Biology Training Grant,T32AI007413)

  • Peter K Kim
  • Samuel A Kerk

Thompson Family Foundation (Research Grant)

  • Kayvan R Keshari

STARR Cancer Consortium (Research Grant)

  • Kayvan R Keshari

National Cancer Institute (Cancer Center Support Grant,P30CA008748)

  • Kayvan R Keshari

American Association for Cancer Research (Pathway to Leadership award,13-70-25-LYSS)

  • Costas Lyssiotis

V Foundation for Cancer Research (Junior Scholar Award,V2016-009)

  • Costas Lyssiotis

Sidney Kimmel Foundation (Kimmel Scholar Award,SKF-16-005)

  • Costas Lyssiotis

American Association for Cancer Research (NextGen Grant for Transformative Cancer Research,17-20-01-LYSS)

  • Costas Lyssiotis

National Cancer Institute (Cancer Center Support Grant,P30 CA046592)

  • Costas Lyssiotis

National Cancer Institute (R37CA237421)

  • Costas Lyssiotis

National Cancer Institute (R01CA248160)

  • Costas Lyssiotis

National Cancer Institute (Predoctoral Fellowship,F31CA243344)

  • Peter K Kim

National Cancer Institute (R01CA244931)

  • Costas Lyssiotis

National Institutes of Health (U24DK097153)

  • Costas Lyssiotis

Charles Woodson Research Fund (Research Support)

  • Costas Lyssiotis

UM Pediatric Brain Tumor Initiative (Research Support)

  • Costas Lyssiotis

National Cancer Institute (F99/K00CA264414)

  • Samuel A Kerk

National Institute of Child Health and Human Development (T32HD007505)

  • Megan Radyk

National Cancer Institute (Pathway to Independence Award,K99CA241357)

  • Christopher J Halbrook

National Institute of Diabetes and Digestive and Kidney Diseases (Postdoctoral Support,P30DK034933)

  • Christopher J Halbrook

National Cancer Institute (F31CA24745701)

  • Samuel A Kerk

National Cancer Institute (R01CA237466)

  • Kayvan R Keshari

National Cancer Institute (R01CA252037)

  • Kayvan R Keshari

National Cancer Institute (R21CA212958)

  • Kayvan R Keshari

Stand Up To Cancer (Research Grant)

  • Kayvan R Keshari

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lydia W S Finley, Memorial Sloan Kettering Cancer Center, United States

Ethics

Animal experimentation: Animal experiments were conducted in accordance with the Office of Laboratory Animal Welfare and approved by the Institutional Animal Care and Use Committees of the University of Michigan. Protocol#: PRO00008877

Version history

  1. Received: September 1, 2020
  2. Accepted: December 21, 2021
  3. Accepted Manuscript published: December 24, 2021 (version 1)
  4. Accepted Manuscript updated: December 29, 2021 (version 2)
  5. Version of Record published: January 5, 2022 (version 3)

Copyright

© 2021, Kim et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Peter K Kim
  2. Christopher J Halbrook
  3. Samuel A Kerk
  4. Megan Radyk
  5. Stephanie Wisner
  6. Daniel M Kremer
  7. Peter Sajjakulnukit
  8. Anthony Andren
  9. Sean W Hou
  10. Ayush Trivedi
  11. Galloway Thurston
  12. Abhinav Anand
  13. Liang Yan
  14. Lucia Salamanca-Cardona
  15. Samuel D Welling
  16. Li Zhang
  17. Matthew R Pratt
  18. Kayvan R Keshari
  19. Haoqiang Ying
  20. Costas Lyssiotis
(2021)
Hyaluronic acid fuels pancreatic cancer cell growth
eLife 10:e62645.
https://doi.org/10.7554/eLife.62645

Share this article

https://doi.org/10.7554/eLife.62645

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