Trop2 modulates beta1 integrin-mediated adhesion and migration of prostate cancer cells

Trop1 and Trop2 are highly related transmembrane glycoproteins, which are overexpressed in many human carcinomas and have been suggested to contribute to cancer progression. Recently, Trop2 has been discovered as an important marker for identification of candidate tumor-initiating cells in a mouse model of prostate cancer (PrCa), suggesting that this protein is a novel regulator of PrCa progression. In this study, we show that Trop2 was expressed at high levels in aggressive human PrCa cells, and was colocalized with beta1 integrins, which are known to modulate cell adhesion and invasion and to be deregulated in PrCa. We demonstrate that Trop2 inhibited adhesion of PC3 PrCa cells on fibronectin (the major ligand for beta1), but strongly enhanced their ability to migrate on fibronectin as compared to controls. This effect was specific for cells seeded on fibronectin, since no effect was observed on vitronectin. Confocal microscopy studies using PC3 cells seeded on fibronectin showed strong co-localization of Trop2 with beta1 in leading edges. On the other hand, Trop2 did not co-localize with beta5, an integrin that did not affect migration of PC3 cells on fibronectin. We did not observe any change of beta1 expression in Trop2- overexpressing PC3 cells compared to controls, suggesting that affinity for fibronectin or clustering in focal complexes might be modulated by Trop2. Our studies on Trop2-overexpressing PC3 cells seeded on fibronectin demonstrated that beta1 was in fact displaced from focal adhesions to relocate to Trop2-containing leading edges.