Ovarian carcinoma (OC) broadly describes epithelial tumors involving the ovary and represents the most lethal gynecologic malignancy. The most frequently diagnosed OCs are high-grade serous carcinomas (HGSC), and the majority of these cancers are diagnosed at late stage, stage III or IV (51% and 29% respectively), with widespread disease dissemination. In addition, a significant number of patients develop malignant ascites. A key feature of tumor cells in present in ascites is the capacity to form multicellular aggregates that promote tumor cell survival and continued disease growth and spread. Cell adhesion molecule (CAM)-related downregulated by oncogenes (CDON) is a cell surface glycoprotein with established roles in normal development and associated with some tumor types. CDON signaling occurs via ligand-dependent mechanisms as a hedgehog co-receptor and ligand-independent mechanisms via interactions with cadherins. Little is known about the role of CDON in ovarian cancer, but given the importance of cadherin-mediated cell adhesion in disease dissemination, we asked whether CDON plays a role in HGSC growth and progression. We find that CDON is expressed in ovarian carcinoma (OC) cells, and protein levels are elevated by expression of oncogenes or by growth under nonadherent conditions. Depletion of CDON expression revealed that it plays an important role in HGSC cells regardless of growth conditions, resulting in decreased growth (proliferation) in cells grown under nonadherent conditions as multicellular aggregates or under adherent conditions as 2D monolayers. Alterations in signaling related to both cell adhesion and survival occur upon CDON downregulation, including decreased cadherin protein expression, integrin expression, and focal adhesion kinase activation. Depletion of CDON in OC cells results in significant tumor growth inhibition in xenograft and allograft models, suggesting that CDON plays an important role in promoting ovarian tumor growth. Treatment of OC spheroids with novel anti-CDON antibodies results in collapse of 3D cellular structures and induction of apoptosis, supporting a key role for CDON in OC cellular adhesion in tumor cell survival. These data indicate that CDON may play an essential role in OC spread since altered cell-cell adhesion and survival as multicellular aggregates is crucial for disease dissemination in patients. Taken together, our results nominate CDON as an important protein promoting HGSC growth and progression and as a novel therapeutic target for the treatment of this disease.

Citation Format: Valerie L. Sodi, Shane W. O'Brien, Chao Wu, Roland L. Dunbrack, Tiffiney R. Hartman, Alana M. O'Reilly, Denise C. Connolly. Cell adhesion molecule (CAM)-related downregulated by oncogenes (CDON) promotes ovarian cancer adhesion and survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A24.

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.