Abstract 313: Examining the role of ABCA1 cholesterol transporter in ovarian cancer spheroids

Abstract

Abstract Epithelial ovarian cancer (EOC) is a devastating disease which accounts for a large proportion of gynaecological cancer-related deaths. Poor survival is largely due to late diagnosis of the disease which typically presents with peritoneal dissemination. In order to achieve reduced tumor burden and improved survival, it is imperative to identify new prognostic markers and potential therapeutic targets. Recent work by our group identified high ATP- Binding Cassette A1 (ABCA1) transporter expression as being associated with poor outcome in EOC. ABCA1 has been widely studied as a cholesterol transporter, however there is little research investigating its potential roles in cancer biology. The aim of this work was to ascertain whether ABCA1 may promote aggressive characteristics in EOC. siRNA-mediated suppression of ABCA1 in EOC cell lines led to reduced colony forming ability, growth and migration by comparison with controls. By culturing EOC cell lines (Skov3, 27/87 and HEY) in a 3-dimensional spheroid model, we have shown that ABCA1 suppression significantly reduced overall spheroid volume (p = ≤0.0003, ANOVA with Dunnett's multiple comparison test). In Skov3 and 27/87 spheroids, reduced volume was associated with cell death; however in HEY spheroids, ABCA1 suppression significantly reduced cell numbers in the absence of detectable cell death (p = ≤0.0002, ANOVA with Dunnett's multiple comparison test). Detailed characterisation of spheroid architecture revealed an increased volume-to-cell ratio in those depleted of ABCA1, indicating a lower degree of compaction compared to controls. It was further observed that whilst HEY spheroids derived from control siRNA-transfected cells develop a prominent necrotic core this feature was dramatically impaired by ABCA1 suppression. Compaction and core necrosis are both well-documented processes in spheroid biology that are indicative of cellular contractility and a hypoxic tumour environment, both key characteristics of more aggressive, chemo-resistant and recurrent tumors. Collectively these data suggest that ABCA1 may be involved in regulating multiple processes associated with aggressive and invasive characteristics of EOC, highlighting ABCA1 as a potential therapeutic target. Citation Format: Rebekka Williams, Amanda Russell, Angelika Bongers, Sharon Sagnella, Christopher Fife, Wendy Jessup, Anna DeFazio, Georgia Chenevix-Trench, Michelle Haber, Murray Norris, Michelle Henderson. Examining the role of ABCA1 cholesterol transporter in ovarian cancer spheroids. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 313. doi:10.1158/1538-7445.AM2015-313