Tumor and Stem Cell Biology Trop-2 Promotes Prostate Cancer Metastasis ByModulating b1 Integrin Functions

Themolecular mechanisms underlying metastatic dissemination are still not completely understood.We have recently shown that b1 integrin-dependent cell adhesion to fibronectin and signaling is affected by a transmembrane molecule, Trop-2, which is frequently upregulated in human carcinomas. Here, we report that Trop-2 promotesmetastatic dissemination of prostate cancer cells in vivo and is abundantly expressed inmetastasis from human prostate cancer. We also show here that Trop-2 promotes prostate cancer cell migration on fibronectin, a phenomenon dependent on b1 integrins. Mechanistically, we demonstrate that Trop-2 and the a5b1 integrin associate through their extracellular domains, causing relocalization ofa5b1 and the b1-associatedmolecule talin from focal adhesions to the leading edges. Trop-2 effect is specific as this molecule does not modulate migration on vitronectin, does not associate with the major vitronectin receptor, avb3 integrin, and does not affect localization of avb3 integrin as well as vinculin in focal adhesions. We show that Trop-2 enhances directional prostate cancer cell migration, throughmodulation of Rac1 GTPase activity. Finally, we show that Trop-2 induces activation of PAK4, a kinase that has been reported tomediate cancer cellmigration. In conclusion, we provide the first evidence that b1 integrin-dependent migratory and metastatic competence of prostate cancer cells is enhanced by Trop-2. Cancer Res; 73(10); 1–13. 2013 AACR.