Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, United States; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Christopher J Halbrook
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Samuel A Kerk
Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, United States; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Megan Radyk
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Stephanie Wisner
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Daniel M Kremer
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States; Program in Chemical Biology, University of Michigan, Ann Arbor, United States
Peter Sajjakulnukit
Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, United States; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Anthony Andren
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Sean W Hou
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Ayush Trivedi
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Galloway Thurston
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Abhinav Anand
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Liang Yan
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, United States
Lucia Salamanca-Cardona
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, United States
Samuel D Welling
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Li Zhang
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, United States
Department of Chemistry, University of Southern California, Los Angeles, United States; Department of Biological Sciences, University of Southern California, Los Angeles, United States
Kayvan R Keshari
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
Haoqiang Ying
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, 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
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.
