2. Academic Validation
  3. Uridine phosphorylase-1 supports metastasis by altering immune and extracellular matrix landscapes

Uridine phosphorylase-1 supports metastasis by altering immune and extracellular matrix landscapes

  • EMBO Rep. 2025 Jul 23. doi: 10.1038/s44319-025-00520-7.
Declan Whyte 1,  Sophie L Fisher 1 2,  Christopher G J McKenzie 1,  David Sumpton 1 2,  Sandeep Dhayade 1,  Emmanuel Dornier 1,  Madeleine Moore 1,  David Novo 1,  Jasmine Peters 1 2,  Robert Wiesheu 1 2,  Michalis D Gounis 1,  Dale M Watt 1,  John B G Mackey 1,  Amanda J McFarlane 1,  Frédéric Fercoq 1,  Carolina Dehesa Caballero 2,  Keara L Redmond 3,  Louise E Mitchell 1,  Eve Anderson 1,  Gemma Thomson 1,  Ann Hedley 1,  William Clark 1,  Shannen Leroi 2,  Lindsey N Dzierozynski 4,  Juan J Apiz Saab 4,  Caroline A Lewis 5,  Alexander Muir 4,  Christopher J Halbrook 6 7,  Douglas Strathdee 1,  Rene Jackstadt 1,  Colin Nixon 1,  Philip Dunne 1 3,  Leo M Carlin 1 2,  Iain R Macpherson 2,  Edward W Roberts 1 2,  Seth B Coffelt 1 2,  Karen Blyth 1 2,  Owen J Sansom 1 2,  Jim C Norman 8 9,  Johan Vande Voorde 10 11,  Cassie J Clarke 12 13
Affiliations

Affiliations

  • 1 Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
  • 2 School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK.
  • 3 Queen's University Belfast, University Rd, Belfast, BT7 1NN, UK.
  • 4 Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
  • 5 Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • 6 Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.
  • 7 Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA, USA.
  • 8 Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. j.norman@crukscotlandinstitute.ac.uk.
  • 9 School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK. j.norman@crukscotlandinstitute.ac.uk.
  • 10 Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. johan.vandevoorde@glasgow.ac.uk.
  • 11 School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK. johan.vandevoorde@glasgow.ac.uk.
  • 12 Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. c.clarke@crukscotlandinstitute.ac.uk.
  • 13 School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK. c.clarke@crukscotlandinstitute.ac.uk.
PMID: 40702342 DOI: 10.1038/s44319-025-00520-7
Abstract

Understanding mechanisms that facilitate early events in metastatic seeding is key to developing therapeutic approaches to reduce metastasis. Here we identify uracil as a metastasis-associated metabolite in genetically engineered mouse models of Cancer and in patients with metastatic breast Cancer. Uracil is generated by the enzyme uridine phosphorylase-1 (UPP1), and we find that neutrophils are a significant source of UPP1 in metastatic Cancer. Mammary tumours increase expression of adhesion molecules on the neutrophil surface, in a UPP1-dependent manner, leading to decreased neutrophil motility in the pre-metastatic lung. UPP1-expressing neutrophils suppress T-cell proliferation, and the UPP1 product uracil increases fibronectin deposition in the extracellular microenvironment. Knockout or inhibition of UPP1 in mice with mammary tumours increases T-cell numbers and reduces fibronectin content in the lung, and decreases the proportion of mice that develop lung metastasis. These data indicate that UPP1 influences neutrophil behaviour and extracellular matrix deposition in the lung, and suggest that circulating uracil could be a marker of metastasis, and that pharmacological inhibition of UPP1 could be a strategy to reduce recurrence.

Keywords

Fibronectin; Metastasis; Neutrophils; T Cells; Uridine Phosphorylase.

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