Abstract 989: NEDD9 expression promotes epithelial ovarian cancer growth and dissemination (2014)

Abstract NEDD9 (Neural precursor cell Expressed, Developmentally Downregulated 9) is a scaffolding protein with roles in focal adhesion signaling, cell motility and regulation of centrosome function. NEDD9 has been reported as an important player in development and progression of several different solid tumors; however, its role in gynecologic cancers is poorly understood. In this study we investigated the role of NEDD9 in development and progression of epithelial ovarian cancer (EOC) using murine models. Three mouse strains were used: MISIIR-TAg mice that develop spontaneous ovarian carcinomas; MISIIR-TAg-Low mice that express the TAg transgene, but do not develop tumors; and Nedd9 null mice. To determine the effects of loss of Nedd9 on ovarian carcinoma development, MISIIR-TAg and Nedd9-/- mice were crossed and spontaneous ovarian tumor growth in MISIIR-TAg;Nedd9-/- and MISIIR-TAg;Nedd9+/+ mice was monitored and quantified by longitudinal magnetic resonance imaging (MRI). MISIIR-TAg-Nedd9-/- mice, compared to MISIIR-TAg-Nedd9+/+ mice, exhibited delayed tumor development and decreased tumor burden. Correspondingly, microarray analysis of tumors showed that several key oncogenic signaling pathways were upregulated in MISIIR-TAg-Nedd9+/+ mice compared to MISIIR-TAg-Nedd9-/- mice. Murine ovarian carcinoma (MOVCAR) cell lines were established from MISIIR-TAg-Nedd9-/- and MISIIR-TAg-Nedd9+/+ mice and essential tumorigenic features compared using in vitro assays. Interestingly, although these cells displayed no differences in adhesion or proliferation, Nedd9-/- MOVCAR cells were more aggressive than Nedd9+/+ cells in assays of migration and invasion. However, when grown as orthotopic allografts in permissive MISIIR-TAg-Low;Nedd9+/+ hosts, in vivo tumor growth was delayed and the number of metastatic tumor nodules was decreased in mice engrafted with Nedd9-/- cells compared to those injected with Nedd9+/+ cells. To study the potential role of Nedd9 in the tumor microenvironment, immune cell populations were compared in: 1) orthotopic allografts of Nedd9+/+ MOVCAR cells grown in MISIIR-TAg-Low;Nedd9-/- and MISIIR-TAg-Low;Nedd9+/+ hosts; or 2) spontaneous ovarian tumors in MISIIR-TAg-Nedd9-/- and MISIIR-TAg-Nedd9+/+ mice. In the allograft model, the number and total volume of metastatic tumor nodules was not significantly different in Nedd9-/- or Nedd9+/+ hosts; however, genotype-associated differences in tumor infiltrating NK-cell numbers were observed. Comparison of the spontaneous tumor models showed that the number of tumor infiltrating macrophages and NK-cells were decreased in MISIIR-TAg-Nedd9-/- mice. Collectively, these data suggest that Nedd9 promotes development and progression of EOC, through induction of oncogenic signaling and by pro-tumorigenic alterations of the immune cell microenvironment. Citation Format: Rashid Gabbasov, Laura E. Bickel, Shane W. O'Brien, Samuel Litwin, Sachiko Seo, Erica A. Golemis, Denise C. Connolly. NEDD9 expression promotes epithelial ovarian cancer growth and dissemination. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 989. doi:10.1158/1538-7445.AM2014-989