Hyaluronic acid fuels pancreatic cancer cell growth

eLife

Matthew R Pratt¹  Sean W Hou²  Stephanie Wisner²  Anthony Andren²  Samuel D Welling²  Galloway Thurston²  Abhinav Anand²  Christopher J Halbrook²  Megan Radyk²  Ayush Trivedi²  Li Zhang²  Costas A Lyssiotis³  Daniel M Kremer⁴  Liang Yan⁵  Haoqiang Ying⁵  Lucia Salamanca-Cardona⁶  Kayvan R Keshari⁷  Peter K Kim⁸  Peter Sajjakulnukit⁸  Samuel A Kerk⁸ 

[1] Department of Chemistry, University of Southern California, Los Angeles, United States;Department of Biological Sciences, University of Southern California, Los Angeles, United States;Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States;Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States;Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, United States;Rogel Cancer Center, University of Michigan, Ann Arbor, United States;Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States;Program in Chemical Biology, University of Michigan, Ann Arbor, United States;Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, United States;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, United States;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, United States;Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York City, United States;Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, United States;Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States;

关键词: pancreatic cancer;    tumor metabolism;    tumor microenvironment;    extracellular matrix;    hyaluronic acid;    hexosamine biosynthetic pathway;    Human;    Mouse;   

DOI  :  10.7554/eLife.62645

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY