Abstract 2850: Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma

Abstract

Cadherin 6 (CDH6) is a type II cadherin containing a RGD motif in a similar way to LI-cadherin (CDH17) and VE-cadherin (CDH5), which are able to activate α2β1 integrin signalling to promote lung and liver metastasis. CDH6 gene is frequently overexpressed in late stages of some types of ovarian carcinoma, clear cell renal carcinoma, renal papillary carcinoma and thyroid cancers. Therefore, as reported for CDH17 and CDH5, we hypothesized that CDH6 might be a potential therapeutic target for metastatic ovarian cancer. Indeed, an “in silico” analysis revealed a significant association between CDH6 expression, tumour stage and poor survival in renal and ovarian cancer patients. We confirmed a high CDH6 expression in ovarian cancer cell lines, although with significant differences in cell surface availability, as determined by flow cytometry. In addition, we noticed a variable α2β1 integrin expression in the same cell lines. Indeed, CDH6 RGD peptide caused β1 integrin activation in OVCAR3 cells but not in SKOV-3, suggesting the existence of alternative mechanisms. In this regard, as CDH6 has been reported to be a αIIbβ3 integrin ligand in platelets, we investigated and confirmed the expression of αIIbβ3 integrin in SKOV3 but not in OVCAR3 cells. Remarkably, CDH6 was able to activate αIIbβ3 integrin in SKOV3 cells. Moreover, silencing of CDH6 or β3 integrin triggered a significant loss of prometastatic traits in ovarian cells, such as cell adhesion, migration, invasion and proliferation. Signalling pathway analysis demonstrated that β3 integrin activation was triggering the phosphorylation of AKT and SRC, but not FAK, promoting cell invasion. Finally, treatment with monoclonal antibodies against the cadherin RGD motif inhibited the metastatic behaviour in ovarian cancer cell lines “in vitro”. Experiments with metastatic mouse models to confirm the inhibitory capacity of cadherin RGD-specific monoclonal antibodies are in progress. In summary, these findings suggest that CDH6 RGD motif could activate α2β1 or αIIbβ3 integrins, according to the cell context, and be targeted to avoid metastatic dissemination and cancer progression in those ovarian tumours overexpressing CDH6. Citation Format: Miranda Burdiel, Ruben Bartolome, Marta Jaen, Ignacio Casal. Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2850.