Abstract PR10: Uridine-to-ribose axis supports glucose-restricted pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year survival rate of 12% in the USA. PDA highly rely on glucose but is surrounded by a nutrient-limited microenvironment. How PDA survive such condition, and the metabolites enabling that process, is unclear. To determine how PDA adapt to starvation, we profiled the utility of >175 metabolites by 21 pancreatic cell lines cultured in glucose limited condition. This nutrient profiling assay revealed that PDA use uridine when glucose is depleted. Uridine utilization strongly correlated with uridine phosphorylase 1 (UPP1) – the enzyme that breaks down uridine to uracil and ribose-1-phosphate. Metabolomics, including stable isotope tracing, revealed that when glucose is limited, PDA cells use the ribose from uridine to sustain central carbon metabolism and that this process is blocked upon the knockout of UPP1. We found that UPP1 is regulated by KRAS, is high in PDA, and correlates with poor survival in patients. Moreover, deletion of UPP1 blunted tumor growth in mice. Our data identify the uridine-ribose axis as a crucial compensatory pathway in nutrient-deprived PDA, suggesting a potential therapeutic target. Citation Format: Zeribe C. Nwosu, Matthew H. Ward, Peter Sajjakulnukit, Pawan Poudel, Chanthirika Ragulan, Steven Kasperek, Megan Radyk, Damien Sutton, Rosa E. Menjivar, Anthony Andren, Juan J. Apiz-Saab, Zachary Tolstyka, Kristee Brown, Ho-Joon Lee, Lindsey Dzierozynski, Xi He, Hari Ps, Julia Ugras, Gift Nyamundanda, Li Zhang, Christopher J. Halbrook, Eileen Carpenter, Jiaqi Shi, Leah P. Shriver, Gary J. Patti, Alexander Muir, Marina Pasca di Magliano, Anguraj Sadanandam, Costas A. Lyssiotis. Uridine-to-ribose axis supports glucose-restricted pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR10.