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

Objective:Ovarian cancer is mainly confined in peritoneal cavity and its spread is aided by peritoneal ascites. Lysophosphatidic acid (LPA) is present at high levels in ovarian cancer patients' ascites and potently stimulates cell migration, which faciliate the procession of cancer metastasis. Thus, we hypothesize that LPA-induced cell migration might be a key step in ovarian cancer metastasis, in which the mechanisam in detail is still unkown. Our purpose is to determine the role of LPA in ovarian cancer metastasis, the underling signaling mechanisms and the key factors responsible for the migratory capacity of cancer cells.Methods:Transwell migration and peritoneal metastatic colonization assays were performed to determine the correlation between LPA-stimulated cell migration and metastatic potentials. We compared LPA-induced Rho GTpases activation between metastatic and non-metastatic ovarian cancer cell lines and characterized the involved signaling mechanisms with genetic mutants and shRNAs. Finally, we analyzed the correlation between SOS1/EPS8/ABI1 co-expression and clinical status of ovarian cancer patients by immunohistochemistry.Results:Ovarian cancer cell lines with LPA migratory response were metastatic and vice versa. Among Rho GTPases, Rac activation is essential for LPA-induced cell migration. Because Rac(-) could blocked the LPA response and metastasis of invasive cells (P<0.05); Rac(+) could confer the non-invasive cells with LPA response and metastatic capability (P<0.05).The signaling mechanism study demonstrated that: the pathway responsible for LPA-induced cell migration was LPAR1-Ras-SOS1/EPS8/ABI1-Rac. LPA transduce the migratory signal into the cells through LPAR1 but the other LPA receptors, because knock down the expression of LPAR1 could block the LPA-indcuced cell migration (P<0.05) and Rac activation. Then signal from LPA will active Rac-specific guanine nucleotide exchange factor SOS1. SOS1 forms a tri-complex with EPS8 and ABI1, and active Rac with the coordination of these two proteins. The integrity of SOS1/EPS8/ABI1 tri-complex was necessary for ovarian cancer metastasis, becasue silence any member of the complex could block the LPA-induced Rac activation, cell migration and metastatic colonization (P<0.05). Members of SOS1/EPS8/ABI1 tri-complex were absent in non-metastatic ovarian cancer cells and re-expressing the missing one conferred them with LPA responsiveness and metastatic capability (P<0.05).Importantly, clinical samples detection showed that SOS1/EPS8/ABI1 co-expression correlated to advanced clinic stages (P=0.00l) and shorter survival of ovarian cancer patients (P=0.025).Conclusions:The magritory capability of the ovarian cancer cells is closely correlated to the LPA responsiveness of the cells. The LPA-induced Rac activation is essential for ovarian cancer metastasis, and LPAR1-Ras-SOS1/EPS8/ABIl-Rac signaling pathway is responsible for this biologic effect. The integrity of SOS1/EPS8/ABI1 tri-complex is a determinant of metastatic capability of ovarian cancer cells. Co-expression of SOS1/EPS8/ABI1 might be an reliable indicator of patients'survival. This tri-complex could be a target for anti-cancer treatment.