Hyaluronic acid fuels pancreatic cancer cell growth

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.

‘Two-faces’ of hyaluronan, a dynamic barometer of disease progression in tumor microenvironment

“…This phenomenon was also observed in endocardial endothelial cells, wherein HA endocytosis works as high-energy metabolites to fuel cells [ 142 ]. Recently, a researcher reported that an increase of GlcNAc from HA cleavage remarkably ensures the energy supply in growth of pancreatic cancer cells [ 143 ].…”

PEGPH20, a PEGylated human hyaluronidase, induces radiosensitization by reoxygenation in pancreatic cancer xenografts. A molecular imaging study

“…In breast cancer, HA production shifts metabolic programs toward acceleration of glycolysis, [50] which is regulated by HIF-1 under the control of the hexosamine biosynthetic pathway flux. [51] Consistently, it has been reported that antagonizing hyaluronan-CD44 interactions with HA oligomers inhibits the assembly of MCT1 and MCT4 complexes in the plasma membrane, and consequently suppresses lactate efflux from breast carcinoma cells [52] . In addition, one Phase 1 trial of PEGPH20 evaluating 18 F-FDG-PET/CT showed that 6 out of 9 evaluable patients exhibited decrease in standardized uptake value (SUV), suggesting an upregulation of glycolysis [41] .…”

The role of metabolic reprogramming in pancreatic cancer chemoresistance

“…The combination of PGM3 inhibitor FR054 and GEM increases chemosensitivity and effectively inhibits xenograft tumor growth ( Ricciardiello et al, 2020 ). A recent study showed that hyaluronic acid in PC bypass GFAT1 and promote PC cell growth by replenishing energy for HBP through the GlcNAc salvage pathway ( Kim et al, 2021 ).…”