Hyaluronic acid fuels pancreatic cancer cell growth
Open accessAbstract
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.
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PDAC cells can obtain GlcNAc through N-acetylglucosamine kinase salvage from matrix components, including hyaluronic acid.
“PDAC cells can also obtain GlcNAC through N-acetylglucosamine kinase salvage from matrix components256, including hyaluronic acid257”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [256]
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- Authors
- Kim, P. K., Halbrook, C. J., Kerk, S. A., Radyk, M., Wisner, S., Kremer, D. M., Sajjakulnukit, P., Andren, A., Hou, S. W., Trivedi, A., Thurston, G., Anand, A., Yan, L., Salamanca-Cardona, L., Welling, S. D., Zhang, L., Pratt, M. R., Keshari, K. R., Ying, H., & Lyssiotis, C. A.
- Affiliations
- University of Michigan (US)
- The University of Texas MD Anderson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Southern California (US)
- Corresponding author
- Lyssiotis, Costas A
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-12-24
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8730721
- OpenAlex
- W4200046987
- Cited by
- 92
- References
- 61
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 27 · 2023: 23 · 2022: 13 · 2021: 1
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Cancer Institute (Cancer Biology Training Grant,T32AI007413, Predoctoral Fellowship F31CA243344, Pathway to Independence Award K99CA241357, F31CA24745701, R01CA237466, R01CA252037, R21CA212958, Cancer Center Support Grant P30CA008748, Cancer Center Support Grant P30 CA046592, R37CA237421, R01CA248160, R01CA244931, F99/K00CA264414)
- National Institute of Diabetes and Digestive and Kidney Diseases (Postdoctoral Support P30DK034933)
- Stand Up To Cancer (Research Grant)
- Thompson Family Foundation (Research Grant)
- STARR Cancer Consortium (Research Grant)
- American Association for Cancer Research (Pathway to Leadership award 13-70-25-LYSS, NextGen Grant for Transformative Cancer Research 17-20-01-LYSS)
- V Foundation for Cancer Research (Junior Scholar Award V2016-009)
- Sidney Kimmel Foundation (Kimmel Scholar Award SKF-16-005)
- National Institutes of Health (U24DK097153)
- Charles Woodson Research Fund (Research Support)
- UM Pediatric Brain Tumor Initiative (Research Support)
- National Institute of Child Health and Human Development (T32HD007505)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- hyaluronic acid, pancreatic ductal adenocarcinoma, hexosamine biosynthetic pathway, GFAT1, cancer metabolism, N-acetylglucosamine, tumor microenvironment, tumor cell proliferation, xenograft tumor growth
- MeSH terms
- Adenocarcinoma, Animals, Female, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), Hexosamines, Humans, Hyaluronic Acid, Male, Transplantation, Heterologous, Mice, SCID, Mice, Inbred NOD, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Proliferation, Mice, Gene Knockout Techniques
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