학술논문
Hyaluronic acid fuels pancreatic cancer cell growth
Document Type
article
Author
Peter K Kim; Christopher J Halbrook; Samuel A Kerk; Megan Radyk; Stephanie Wisner; Daniel M Kremer; Peter Sajjakulnukit; Anthony Andren; Sean W Hou; Ayush Trivedi; Galloway Thurston; Abhinav Anand; Liang Yan; Lucia Salamanca-Cardona; Samuel D Welling; Li Zhang; Matthew R Pratt; Kayvan R Keshari; Haoqiang Ying; Costas A Lyssiotis
Source
eLife, Vol 10 (2021)
Subject
Language
English
ISSN
2050-084X
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.