Integrity of SOS1/EPS8/ABI1 Tri-Complex Determines Ovarian Cancer Metastasis

Ovarian cancer is mainly confined in peritoneal cavity and its metastasis is often associated with the formation of malignant ascites. As lysophosphatidic acid (LPA) is present at high levels in ovarian cancer patients ’ ascites and potently stimulates cell migration, we reason that LPA-stimulated cell migration may play an important role in ovarian cancer metastasis. Here, we show that only those ovarian cancer cell lines with LPA migratory response undergo peritoneal metastatic colonization. LPA-stimulated cell migration is required for metastatic colonization because knockdown of LPA receptor 1 (LPAR1) abolishes this event. However, the difference in metastatic potentials is not caused by the absence of LPAR1 because both metastatic and non-metastatic lines express similar level of LPAR1. Instead, we find that LPA can only activate Rac in metastatic cells and that metastatic colonization of ovarian cancer cells necessitates Rac activity. These results thus suggest that LPA-induced Rac activation is a prerequisite for ovarian cancer metastasis. In metastatic cells, Rac activation is facilitated by SOS1/EPS8/ABI1 tri-complex and the integrity of this tri-complex is essential for LPA-stimulated cell migration and metastatic colonization. We show that at least one member of SOS1/EPS8/ABI1 tri-complex is absent in non-metastatic ovarian cancer cells and re-expressing the missing one conferred them with metastatic capability. Importantly, co-expression of SOS1, EPS8 and ABI1, but not the expression of any individual member of SOS1/EPS8/ABI1 tri-complex, correlates with advanced stages and shorter survival of ovarian cancer patients. Our study implicates that the integrity of SOS1/EPS8/ABI1 tri-complex is a determinant of ovarian cancer metastasis