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.

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

Reviewing Editor

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

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.

Metrics

  • 8,048
    Page views
  • 803
    Downloads
  • 31
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Cancer Biology
    2. Computational and Systems Biology
    Jessica Xin Hjaltelin, Sif Ingibergsdóttir Novitski ... Søren Brunak
    Research Article

    Pancreatic cancer is one of the deadliest cancer types with poor treatment options. Better detection of early symptoms and relevant disease correlations could improve pancreatic cancer prognosis. In this retrospective study, we used symptom and disease codes (ICD-10) from the Danish National Patient Registry (NPR) encompassing 6.9 million patients from 1994 to 2018,, of whom 23,592 were diagnosed with pancreatic cancer. The Danish cancer registry included 18,523 of these patients. To complement and compare the registry diagnosis codes with deeper clinical data, we used a text mining approach to extract symptoms from free text clinical notes in electronic health records (3078 pancreatic cancer patients and 30,780 controls). We used both data sources to generate and compare symptom disease trajectories to uncover temporal patterns of symptoms prior to pancreatic cancer diagnosis for the same patients. We show that the text mining of the clinical notes was able to complement the registry-based symptoms by capturing more symptoms prior to pancreatic cancer diagnosis. For example, ‘Blood pressure reading without diagnosis’, ‘Abnormalities of heartbeat’, and ‘Intestinal obstruction’ were not found for the registry-based analysis. Chaining symptoms together in trajectories identified two groups of patients with lower median survival (<90 days) following the trajectories ‘Cough→Jaundice→Intestinal obstruction’ and ‘Pain→Jaundice→Abnormal results of function studies’. These results provide a comprehensive comparison of the two types of pancreatic cancer symptom trajectories, which in combination can leverage the full potential of the health data and ultimately provide a fuller picture for detection of early risk factors for pancreatic cancer.

    1. Cancer Biology
    Gehad Youssef, Luke Gammon ... Adrian Biddle
    Research Article

    Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as CSC markers that, alongside the mesenchymal marker Vimentin, identify EMT CSCs in human oral cancer cell lines. This afforded the opportunity to investigate whether the combination of these three markers can identify disseminating EMT CSCs in actual human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 74 human oral tumours, we see a significant enrichment of EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.