Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Cassie Clarke Jim Norman David Sumpton

PROVIDER: MSV000097229 | MassIVE | Tue Mar 04 04:30:00 GMT 2025

REPOSITORIES: MassIVE

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Mental stress is widely recognized as a significant risk factor for breast cancer, exerting detrimental effects on both progression and prognosis. Its specific role in regulating breast cancer metastasis remains explorable. Herein, we prepared chronic stress models with MMTV-PyMT-derived spontaneous mammary tumor mice and GFP-4T1-transplanted metastatic breast cancer mice, followed by examinations of lung metastasis and single-cell sequencing analysis of the pre-metastatic lung microenvironment. Upon chronic stress stimulation, we observed a notable increase in tumor growth and lung metastasis, which was accompanied by the induction of a novel subtype of neutrophils, designated as cancer-stress primed neutrophils (Neu_CSP), characterized by the overexpression of Ccl3, Ccl4, Cxcl2, Il1r2, and C/ebpβ. Pseudotime trajectory analysis demonstrated that chronic stress caused a shift of neutrophils from the cancer primed neutrophils (Neu_CP) subtype to the Neu_CSP subtype in the lung. The glucocorticoid receptor NR3C1 mediated the stress hormone corticosterone (CORT)-induced expression of C/ebpβ in neutrophils, which thereafter promoted the expression of Ccl3 and Ccl4 at the transcriptional level. The differentiation of neutrophils into the Neu_CSP subtype promoted the lung metastasis of Ccr1+ breast cancer cells via chemotactic interactions between Ccl3/Ccl4 in neutrophils and Ccr1 in cancer cells. We used anti-Ly6G antibody to deplete neutrophils, or applied an optimized CRISPR/Cas9 approach for conditional knockout of Ccl3/Ccl4 in neutrophils, or used BX471 to inhibit CCR1 in breast cancer cells, all significantly reduced lung metastases in breast cancer both in vitro and in vivo. This study not only demonstrates a novel stress-neutrophil-cancer axis promoting lung metastasis in breast cancer, but also provides potential strategies for preventing or reducing lung metastasis by targeting the Neu_CSP subtype of neutrophils or CCR1(+) breast cancer cells.

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets