MassIVE MSV000097229

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

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Description

Understanding mechanisms that facilitate early events in metastatic seeding is key to developing therapeutic approaches to reduce metastasis. We have identified uracil as a prominent 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. UPP1 increases expression of adhesion molecules on the neutrophil surface, 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. Consistently, 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 metastatic disease, and that pharmacological inhibition of UPP1 could be a strategy to reduce metastasis. [doi:10.25345/C5Q81548W] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Fibronectin ; Metastasis ; Neutrophils ; T cells ; Uridine Phosphorylase ; DatasetType:Metabolomics

Contact

Principal Investigators:
(in alphabetical order) 		Cassie Clarke, CRUK Scotland Institute, United Kingdom
David Sumpton, CRUK Scotland Insititue, United Kingdom
Jim Norman, CRUK Scotland Institute, United Kingdom
Submitting User: dsumpton
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