2. Academic Validation
  3. Uridine-derived ribose fuels glucose-restricted pancreatic cancer

Uridine-derived ribose fuels glucose-restricted pancreatic cancer

  • Nature. 2023 Jun;618(7963):151-158. doi: 10.1038/s41586-023-06073-w.
Zeribe C Nwosu # 1,  Matthew H Ward # 1 2 3 4,  Peter Sajjakulnukit # 1,  Pawan Poudel # 5,  Chanthirika Ragulan 5,  Steven Kasperek 1,  Megan Radyk 1,  Damien Sutton 1,  Rosa E Menjivar 6,  Anthony Andren 1,  Juan J Apiz-Saab 7,  Zachary Tolstyka 1,  Kristee Brown 8,  Ho-Joon Lee 1,  Lindsey N Dzierozynski 7,  Xi He 8,  Hari Ps 5,  Julia Ugras 1,  Gift Nyamundanda 5,  Li Zhang 1,  Christopher J Halbrook 1,  Eileen S Carpenter 9,  Jiaqi Shi 10,  Leah P Shriver 2 3 4,  Gary J Patti 2 3 4,  Alexander Muir 7,  Marina Pasca di Magliano 8 11,  Anguraj Sadanandam 12 13,  Costas A Lyssiotis 14 15 16
Affiliations

Affiliations

  • 1 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 2 Department of Chemistry, Washington University in St Louis, St Louis, MO, USA.
  • 3 Department of Medicine, Washington University in St Louis, St Louis, MO, USA.
  • 4 Center for Metabolomics and Isotope Tracing, Washington University in St Louis, St Louis, MO, USA.
  • 5 Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
  • 6 Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.
  • 7 Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
  • 8 Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
  • 9 Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
  • 10 Department of Pathology and Clinical Labs, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 11 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 12 Division of Molecular Pathology, The Institute of Cancer Research, London, UK. anguraj.sadanandam@icr.ac.uk.
  • 13 Centre for Global Oncology, Division of Molecular Pathology, The Institute of Cancer Research, London, UK. anguraj.sadanandam@icr.ac.uk.
  • 14 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
  • 15 Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
  • 16 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. clyssiot@med.umich.edu.
  • # Contributed equally.
PMID: 37198494 DOI: 10.1038/s41586-023-06073-w
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.

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