Abstract B015: CCDC80 as a novel cell intrinsic tumor suppressor protein in high grade serous ovarian cancer

Abstract High grade serous ovarian cancer (HGSC), the most common subtype of epithelial ovarian cancer carries a grim prognosis with about 50% 5-year overall survival rates with modern therapies. Chemotherapy and surgery are still the most important modalities of HGSC treatment and very few targeted therapies are available. Thus, better understanding of molecular pathways and potential targets driving HGSC is key to developing novel therapeutics. Here we study coiled-coil domain containing 80 proteins (CCDC80), also known as DRO1. Little is known about the role of CCDC80 in health and disease. Previous studies have reported that CCDC80 expressed in fibroblasts may act as a tumor suppressor protein. We hypothesized that CCDC80 has a tumor cell intrinsic tumor suppressive role in HGSC. To address this, we performed in vitro cancer cell-based assays including proliferation, apoptosis, migration, and colony formation following CCDC80 knockdown and overexpression in several HGSC cell lines. We found that in cancer cells, CCDC80 plays tumor suppressive roles through inhibiting cell migration and colony formation. CCDC80 is known to be down regulated by oncogenes, and we have found that CCDC80 is transcriptionally down regulated by PAX8, a fallopian tube lineage marker that is an oncogenic master regulator of transcription in this disease. The negative regulation of CCDC80 mediates the oncogenic roles of PAX8 on cell migration and colony formation. Of note, consistent with its role as a lineage marker, PAX8 is also expressed in benign fallopian tube cells, the cell of origin of HGSC, but in fallopian tube cells PAX8 does not regulate CCDC80 and therefore does not play an oncogenic role. To understand the mechanism of the tumor suppressive capabilities of CCDC80, we overexpressed CCDC80 in HGSC cells and performed mass spectrometry to identify differentially expressed proteins. One of the most downregulated proteins upon CCDC80 overexpression was the transmembrane immune checkpoint protein B7-H3, which is currently a target for cancer therapy in clinical development stages. We found that in HGSC, B7-H3 is repressed by CCDC80 and activated by PAX8, and has tumor cell-intrinsic oncogenic capacities, including an anti-apoptotic, a pro-clonogenic and a pro-migratory role. We postulate that there is a correlation between the subcellular localization and the functional role of B7-H3. While the well-known role of B7-H3 as an immune checkpoint protein is mediated by the trans-membranous protein and its extra-cellular domain, in HGSC B7-H3 is intra-cellular, localized to the cellular cytoplasm, and plays tumor cell intrinsic oncogenic roles. Taken together, we reveal a new HGSC tumor suppressor protein, and show its regulation and mode of action. The PAX8/CCDC80/B7-H3 which regulates several oncogenic functions in HGSC could potentially serve in the future as a target for drug development. Citation Format: Aya Saleh, Basem Fares, Lina Korsensky, Liron Berger, Ruth Perets. CCDC80 as a novel cell intrinsic tumor suppressor protein in high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B015.