RT Journal Article
SR Electronic
T1 Nutrient profiling reveals extracellular uridine as a fuel for pancreatic cancer through uridine phosphorylase 1
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.07.447448
DO 10.1101/2021.06.07.447448
A1 Matthew H. Ward
A1 Zeribe C. Nwosu
A1 Pawan Poudel
A1 Steven Kasperek
A1 Zach Tolstyka
A1 Rosa E. Menjivar
A1 Chanthirika Ragulan
A1 Gift Nyamundanda
A1 Li Zhang
A1 Anthony Andren
A1 Christopher J. Halbrook
A1 Eileen S. Carpenter
A1 Marina Pasca di Magliano
A1 Anguraj Sadanandam
A1 Costas A. Lyssiotis
YR 2021
UL http://biorxiv.org/content/early/2021/06/08/2021.06.07.447448.abstract
AB Pancreatic ductal adenocarcinoma (PDA) is a lethal disease characterized by high invasiveness, therapeutic resistance, and metabolic aberrations. Although altered metabolism drives PDA growth and survival, the complete spectrum of metabolites used as nutrients by PDA remains largely unknown. Here, we aimed to determine novel nutrients utilized by PDA. We assessed how >175 metabolites impacted metabolic activity in 19 PDA cell lines under nutrient-restricted conditions. This analysis identified uridine as a novel metabolite driver of PDA survival in glucose-deprived conditions. Uridine utilization strongly correlated with expression of the enzyme uridine phosphorylase 1 (UPP1). Metabolomics profiling, notably 13C-stable isotope tracing, revealed that uridine-derived ribose is the relevant component supporting redox balance, survival, and proliferation in glucose-deprived PDA cells. We demonstrate that UPP1 catabolizes uridine, shunting its ribose component into central carbon metabolism to support glycolysis, the tricarboxylic acid (TCA) cycle and nucleotide biosynthesis. Compared to non-tumoral tissues, we show that PDA tumors express high UPP1, which correlated with poor overall survival in multiple patient cohorts. Further, uridine is enriched in the pancreatic tumor microenvironment, and we demonstrate that this may be provided in part by tumor associated macrophages. Finally, we found that inhibition of UPP1 restricted the ability of PDA cells to use uridine, and that UPP1 knockout impairs tumor growth in vivo. Our data identifies uridine catabolism as a critical aspect of compensatory metabolism in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.Competing Interest StatementC.A.L. has received consulting fees from Astellas Pharmaceuticals and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach. A.S. received grants from Merck, Pierre Fabre and Bristol Myers Squibb and is an inventor on patents on Colorectal cancer classification with differential prognosis and personalized therapeutic responses (PCT/IB2013/060416); Prognostic and treatment response prediction in gastric cancer, Priority Patent CSC/BP7295892; Patient classification and prognostic method (GEP-NET) Priority Patent EP18425009.0; and Molecular predictors of therapeutic response to specific anti-cancer agents (US9506926B2).