CDH6-activated αIIbβ3 crosstalks with α2β1 to trigger cellular adhesion and invasion in metastatic ovarian and renal cancers.

Cadherin 6 (CDH6) is significantly overexpressed in advanced ovarian and renal cancers. However, the role of CDH6 in cancer metastasis is largely unclear. Here, we investigated the impact of CDH6 expression on integrin-mediated metastatic progression. CDH6 preferentially bound to αIIbβ3 integrin, a platelet receptor scarcely expressed in cancer cells, and this interaction was mediated through the cadherin RGD motif. Furthermore, CDH6 and CDH17 were found to interact with α2β1 in αIIbβ3low cells. Transient silencing of CDH6, ITGA2B or ITGB3 genes caused a significant loss of proliferation, adhesion, invasion and lung colonization through the downregulation of SRC, FAK, AKT and ERK signaling. Interaction of αIIbβ3 with CDH6, and subsequent αIIbβ3 activation, promoted activation of α2β1 and cell adhesion in ovarian and renal cancer cells. Additionally, monoclonal antibodies specific to the cadherin RGD motif and clinically-approved αIIbβ3 inhibitors could block pro-metastatic activity in ovarian and renal tumors. In summary, the interaction between CDH6 and αIIbβ3 regulate α2β1-mediated adhesion and invasion of ovarian and renal cancer metastatic cells, and constitutes a therapeutic target of broad potential for treating metastatic progression.