Uridine-derived ribose fuels glucose-restricted pancreatic cancer
Author:
Nwosu Zeribe C.ORCID, Ward Matthew H., Sajjakulnukit PeterORCID, Poudel Pawan, Ragulan Chanthirika, Kasperek StevenORCID, Radyk Megan, Sutton Damien, Menjivar Rosa E., Andren Anthony, Apiz-Saab Juan J., Tolstyka Zachary, Brown Kristee, Lee Ho-JoonORCID, Dzierozynski Lindsey N., He XiORCID, PS Hari, Ugras JuliaORCID, Nyamundanda Gift, Zhang Li, Halbrook Christopher J.ORCID, Carpenter Eileen S., Shi Jiaqi, Shriver Leah P., Patti Gary J.ORCID, Muir Alexander, Pasca di Magliano Marina, Sadanandam AngurajORCID, Lyssiotis Costas A.ORCID
Abstract
AbstractPancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference55 articles.
1. Singhi, A. D., Koay, E. J., Chari, S. T. & Maitra, A. Early detection of pancreatic cancer: opportunities and challenges. Gastroenterology 156, 2024–2040 (2019). 2. Wood, L. D., Canto, M. I., Jaffee, E. M. & Simeone, D. M. Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment. Gastroenterology 163, 386–402.e1 (2022). 3. Ho, W. J., Jaffee, E. M. & Zheng, L. The tumour microenvironment in pancreatic cancer—clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 17, 527–540 (2020). 4. DuFort, C. C., DelGiorno, K. E. & Hingorani, S. R. Mounting pressure in the microenvironment: fluids, solids, and cells in pancreatic ductal adenocarcinoma. Gastroenterology 150, 1545–1557.e2 (2016). 5. Encarnación-Rosado, J. & Kimmelman, A. C. Harnessing metabolic dependencies in pancreatic cancers. Nat. Rev. Gastroenterol. Hepatol. 18, 482–492 (2021).
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