Hyaluronic acid fuels pancreatic cancer cell growth.

Peter K Kim ,Anthony Andren,Haoqiang Ying,Galloway Thurston,Ayush Trivedi,Lucia Salamanca-Cardona,Peter Sajjakulnukit,Li Zhang,Abhinav Anand,Liang Yan,Stephanie Wisner,Samuel D Welling,Sean W Hou ,Megan D Radyk ,Daniel M Kremer ,Christopher J Halbrook ,Kayvan R Keshari ,Samuel A Kerk ,Matthew R Pratt ,Costas A Lyssiotis

doi:10.7554/elife.62645

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.

Highlights

Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest human cancers with no clinically effective treatment options [1]
Pancreatic cancer cells require de novo hexosamine biosynthesis pathway (HBP) fidelity in vitro but not in vivo Previously, we found that mutant Kras transcriptionally activates Gfpt1 expression downstream of MAPK signaling in a murine model of PDA to facilitate HBP activity [6]
glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1) catalyzes the reaction that generates glucosamine 6-phosphate and glutamate from fructose 6-phosphate and glutamine (Figure 1A). In another previous study we demonstrated that PDA cells are dependent on glutamine anaplerosis for proliferation [29]

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest human cancers with no clinically effective treatment options [1]. To survive and proliferate in this nutrient austere tumor microenvironment, the oncogenic driver in PDA, mutant Kras, facilitates the rewiring of PDA metabolism [2,3,4,5]. Kras on the activity of the hexosamine biosynthesis pathway (HBP). The HBP is an evolutionarily conserved pathway that integrates glucose, glutamine, fatty acid, and nucleotide metabolism to generate the final product uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is a crucial donor molecule for glycosylation and O-GlcNAcylation, two essential post-translational modifications required for cellular structure, signaling, and survival [7]. The HBP is the only pathway able to generate

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Conclusion