Hyaluronic acid fuels pancreatic cancer cell growth
- University of Michigan, United States
- The University of Texas MD Anderson Cancer Center, United States
- Memorial Sloan Kettering Cancer Center, United States
- 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
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
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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