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We have shown that CAFs promote lung metastases in the mouse tail vein model when they are clustered with triple negative breast cancer (TNBC) MDA-MB231 cells. Following on this observation, we saw that MDA-MB231-luciferase labeled cells persist at higher levels when present in CAF23\/MDA-MB231 co-clusters compared to MDA-MB231 mono-clusters within the first 3\u00a0days after tail vein injection. This prompted us to investigate whether CAFs aid cancer cell extravasation from capillary venules into the lung parenchyma, which would impart better survival and faster seeding of metastases. Ex vivo lung extravasation assays showed that within the first 8\u201324\u00a0h after tail vein injection, more cells from CAF23\/MDA-MB231 co-clusters extravasated than cells from MDA-MB231 mono-clusters. Using in vitro endothelial binding assays, we determined that CAF\/TNBC co-clusters bind to HUVEC endothelial cells better than TNBC mono-clusters. Single-Cell RNA sequencing identified several genes in the fibrinolysis pathway whose expression increases in TNBC cells when they are clustered with CAFs. One of these genes is\n                    <jats:italic>PLAU<\/jats:italic>\n                    , which encodes the urokinase-type plasminogen activator, uPA. siRNA knockdown of PLAU decreased in vitro TNBC-endothelial cell interactions and ex vivo extravasation of MDA-MB231 mono-clusters, revealing a potential role for CAF-induced factors expressed in TNBC cells, such as uPA\/PLAU, in breast cancer cell extravasation. Our data helps to define the role of CAFs in breast cancer extravasation and highlights the importance of our previous work showing that CAFs promote tumor cell dissemination and metastasis.\n                  <\/jats:p>","DOI":"10.1007\/s10585-026-10411-3","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:48:11Z","timestamp":1780462091000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling the role of urokinase-type plasminogen activator, uPA, and circulating cancer-associated fibroblasts (cCAFs) in breast cancer cell extravasation"],"prefix":"10.1007","volume":"43","author":[{"given":"Angela","family":"Spartz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fazila","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Troness","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol A.","family":"Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorraya","family":"El-Ashry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"issue":"6","key":"10411_CR1","first-page":"477","volume":"74","author":"AN Giaquinto","year":"2024","unstructured":"Giaquinto AN et al (2024) Breast cancer statistics 2024. 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