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Capillary endothelial cells (EC) in the liver and lung are the primary sites of contact for circulating tumour cells during metastasis. Here, we analysed the role of integrin \u03b26 in tumour cells for their interaction with EC. Integrin \u03b26 functions as a heterodimer with integrin \u03b1v. Interestingly, we found that liver and lung EC strongly express fibronectin, a high\u2010affinity ligand of \u03b1v\u03b26. Expression of <jats:italic>ITGB6<\/jats:italic> in CRC tumour cells closely correlated with their adhesion to EC. This interaction was greatly reduced by silencing <jats:italic>ITGB6<\/jats:italic> in the tumour cells and was integrin \u03b26 dependent under both static and flow conditions. Binding assays with fibronectin\u2010coated surfaces, competing RGD peptides, and integrin \u03b26\u2010neutralizing antibodies confirmed the crucial role of \u03b26\u2010fibronectin binding in the interaction between tumour cells and EC. Since metastatic tumours exhibit increased proteolytic activity, we examined integrin \u03b26 stability under these conditions. Remarkably, \u03b26 remained resistant to trypsin and the matrix metalloprotease 12, underscoring its role in maintaining tumour cell adhesion in proteolytic microenvironments. Furthermore, ITGB6 expression was significantly elevated in liver metastases compared to corresponding primary tumours from the same patients, suggesting an enrichment of \u03b26\u2010expressing cells in metastatic sites. These results suggest that tumour cell integrin \u03b26 binding to EC\u2010derived fibronectin may serve as a critical first step in metastasis formation. Targeting this interaction could provide a promising therapeutic strategy to repress CRC metastasis.<\/jats:p>","DOI":"10.1002\/ijc.35504","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T08:16:44Z","timestamp":1749457004000},"page":"1481-1495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Integrin \u03b26 expression in colorectal cancer cells promotes liver metastasis through enhanced adhesion to endothelial fibronectin"],"prefix":"10.1002","volume":"157","author":[{"given":"Chiara Van","family":"Passen","sequence":"first","affiliation":[{"name":"Division of Molecular and Experimental Surgery, Uniklinikum Erlangen Friedrich\u2010Alexander\u2010Universit\u00e4t (FAU) Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Krug","sequence":"additional","affiliation":[{"name":"Division of Molecular and 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