Author
Listed:
- Zeribe C. Nwosu
(University of Michigan)
- Matthew H. Ward
(University of Michigan
Washington University in St Louis
Washington University in St Louis
Washington University in St Louis)
- Peter Sajjakulnukit
(University of Michigan)
- Pawan Poudel
(The Institute of Cancer Research)
- Chanthirika Ragulan
(The Institute of Cancer Research)
- Steven Kasperek
(University of Michigan)
- Megan Radyk
(University of Michigan)
- Damien Sutton
(University of Michigan)
- Rosa E. Menjivar
(University of Michigan)
- Anthony Andren
(University of Michigan)
- Juan J. Apiz-Saab
(University of Chicago)
- Zachary Tolstyka
(University of Michigan)
- Kristee Brown
(University of Michigan)
- Ho-Joon Lee
(University of Michigan)
- Lindsey N. Dzierozynski
(University of Chicago)
- Xi He
(University of Michigan)
- Hari PS
(The Institute of Cancer Research)
- Julia Ugras
(University of Michigan)
- Gift Nyamundanda
(The Institute of Cancer Research)
- Li Zhang
(University of Michigan)
- Christopher J. Halbrook
(University of Michigan)
- Eileen S. Carpenter
(University of Michigan)
- Jiaqi Shi
(University of Michigan)
- Leah P. Shriver
(Washington University in St Louis
Washington University in St Louis
Washington University in St Louis)
- Gary J. Patti
(Washington University in St Louis
Washington University in St Louis
Washington University in St Louis)
- Alexander Muir
(University of Chicago)
- Marina Pasca di Magliano
(University of Michigan
University of Michigan)
- Anguraj Sadanandam
(The Institute of Cancer Research
The Institute of Cancer Research)
- Costas A. Lyssiotis
(University of Michigan
University of Michigan
University of Michigan)
Abstract
Pancreatic 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.
Suggested Citation
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 & Z, 2023.
"Uridine-derived ribose fuels glucose-restricted pancreatic cancer,"
Nature, Nature, vol. 618(7963), pages 151-158, June.
Handle:
RePEc:nat:nature:v:618:y:2023:i:7963:d:10.1038_s41586-023-06073-w
DOI: 10.1038/s41586-023-06073-w
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