Integrin β6 expression in colorectal cancer cells promotes liver metastasis through enhanced adhesion to endothelial fibronectin

Abstract Integrin β6 is associated with poor prognosis in colorectal cancer (CRC) patients, with metastasis being a crucial determinant. 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 β6 in tumour cells for their interaction with EC. Integrin β6 functions as a heterodimer with integrin αv. Interestingly, we found that liver and lung EC strongly express fibronectin, a high‐affinity ligand of αvβ6. Expression of ITGB6 in CRC tumour cells closely correlated with their adhesion to EC. This interaction was greatly reduced by silencing ITGB6 in the tumour cells and was integrin β6 dependent under both static and flow conditions. Binding assays with fibronectin‐coated surfaces, competing RGD peptides, and integrin β6‐neutralizing antibodies confirmed the crucial role of β6‐fibronectin binding in the interaction between tumour cells and EC. Since metastatic tumours exhibit increased proteolytic activity, we examined integrin β6 stability under these conditions. Remarkably, β6 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 β6‐expressing cells in metastatic sites. These results suggest that tumour cell integrin β6 binding to EC‐derived fibronectin may serve as a critical first step in metastasis formation. Targeting this interaction could provide a promising therapeutic strategy to repress CRC metastasis.