Abstract
Pancreatic ductal adenocarcinomas (PDACs) have enhanced nutrient uptake requirements and rapid metabolic processing. The enzyme UDP-glucose pyrophosphorylase 2 (UGP2) rests at the convergence of multiple metabolic pathways, however the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an essential role for UGP2 in the maintenance of PDAC growth in both in vitro and in vivo tumor models. Transcription of UGP2 is directly regulated by the YAP/TEAD complex. Loss of UGP2 leads to decreased intracellular glycogen and defects in N-glycosylation targets important for cell growth including epidermal growth factor receptor (EGFR). In murine xenograft models, knockdown of UGP2 halted tumor growth and repressed expression of EGFR. The critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer new avenues of therapy for otherwise intractable PDACs.
Impact Statement Convergent findings reveal that UDP-glucose pyrophosphorylase 2 has a central role in growth and metabolism of pancreatic ductal adenocarcinomas, highlighting novel therapeutic possibilities for this deadly cancer.
Competing Interest Statement
M.S. has received research funds from Puma Biotechnology, AstraZeneca, Daiichi Sankyo, Immunomedics, Targimmune and Menarini Ricerche. He is in the scientific advisory board of Menarini Ricerche and Bioscience Institute and is a cofounder of medendi.org. F.M. is a consultant for Daiichi-Sankyo, Pfizer, Amgen and has received research funding from Daiichi Sankyo. The other authors declare no potential conflicts of interest.