And the original publication is here:
Uridine phosphorylase-1 supports metastasis by altering immune and extracellular matrix landscapes | EMBO reports share.google/JXMzGDRzpl0E...

This work has been highly collaborative & I thank all co-authors,collaborators,facilities & funders.Special thanks to Declan Whyte & Jim Norman for their invaluable contributions & #CRUK @cruk-si.bsky.social, @breastcancernow.bsky.social & @pancreaticcanuk.bsky.social for making this possible(14/14)

Exciting clinical opportunities from these observations include understanding whether circulating #uracil can be used as a #biomarker to detect metastatic disease, & whether UPP1 inhibitors can decrease the risk of distant metastasis &/or improve responses to immunotherapy (13/14)

Collectively our data show that #neutrophils are a significant source of UPP1 in cancer, that UPP1 influences the immunosuppressive & motile behaviour of neutrophils & ECM deposition in lung, & in the absence of UPP1 the ability of mammary tumours to metastasise is reduced (12/14)

And indeed, we found that, in mouse models of #mammary #cancer, knockout of UPP1 decreases the proportion of mice with lung metastasis, whilst knockout of UPP1 in mouse models of #pancreatic #cancer decreases local invasion at the primary tumour (11/14)

Thus far our data indicated that UPP1 can influence neutrophil behaviour, T-cell number and ECM deposition in the lungs of tumour-bearing mice, suggesting that UPP1 can make key contributions to establishment of #niches that support progression of #metastatic disease…. (10/14)

Mechanistically, extracellular uracil supported increased recycling of cell surface receptors in fibroblasts, including fibronectin receptor integrin a5b1, resulting in deposition of a fibronectin-rich matrix that supported increased invasive potential of cancer cells (9/14)

#ECM deposition is also a key feature of niche priming. We found that deposition of #fibronectin in the metastatic lung was reduced in the absence of #UPP1 & that #uracil (derived from UPP1-expressing neutrophils) can directly influence the ECM deposited by #fibroblasts (8/14)

In line with this, we find that whilst UPP1-expressing neutrophils from tumour-bearing mice can inhibit T-cell proliferation, neutrophils from tumour-bearing mice that lack UPP1 have a reduced ability to inhibit T-cell proliferation (7/14)

We hypothesised that UPP1-driven alterations to neutrophil phenotype might also affect the landscape of other immune cell types in metastatic target organs. In the absence of UPP1 we found there was an increase in the number of IL-2+ T Cells in the metastatic lung (6/14)

Neutrophils play key roles in #niche #priming. We thus investigated how UPP1 influences neutrophils in metastatic target organs. Building on the work of @bair-head.bsky.social lab, we found that tumour-induced alterations to neutrophil motility were dependent on UPP1 expression/activity (5/14)

We find that primary tumours increase expression of UPP1 in neutrophils, that uracil derived from UPP1-catalysed cleavage of uridine is secreted from neutrophils into the extracellular environment & depletion of neutrophils from tumour-bearing mice decreases serum uracil (4/14)

Uracil is generated by the enzyme #UPP1. Whilst previous studies, including the beautiful work of @lyssiotislab.bsky.social and @jourdainlab.bsky.social have focused on tumour-specific UPP1, we have found that #neutrophils are a significant source of UPP1 in metastatic cancer (3/14)

To identify #metabolites associated with #metastasis we characterised the circulating metabolome of genetically engineered mouse models of cancer, and found the metabolite #uracil to positively correlate with metastasis in models of breast, pancreatic & colon cancer (2/14)