Abstract POSTER-BIOL-1309: Beta-catenin regulated ALDH1A1 is a target in ovarian cancer stem cells

Abstract

Abstract Spheroids are 3D multi-cell aggregates formed in non-adherent culture conditions. In ovarian cancer (OC), they serve as a vehicle for cancer cell dissemination in the peritoneal cavity and protect cells from extracellular stress-induced anoikis. We hypothesized that spheroids are enriched in cancer stem cells and investigated pathways activated under these conditions. Affymetrix-based gene expression profiling of OC cells grown as spheroids vs. monolayers identified β-catenin pathway being upregulated in 3D cultures. Increased expression of β-catenin and target genes (cyclin D1, c-myc) was demonstrated in spheroids vs. monolayers and in successive spheroid generations using OC cell lines and primary cultures. B-catenin function measured as TCF/LEF1 reporter activity was augmented in spheroids vs. monolayers and siRNA mediated β-catenin knock down decreased the number of spheroids (p<0.001). Along with β-catenin, the expression level of ALDH1A1, an OC stem cell marker, was increased in successive spheroid generations. The percentage of ALDH+ cells was significantly higher in spheroids vs. monolayers in IGROV1, A2780, SKOV3, and primary OC cells. B-catenin knock-down decreased ALDH1A1 expression, suggesting that it is a β-catenin target. The percentage of ALDH+ cells and the number of spheroids formed were increased in the cell population dissociated from OC xenografts treated with carboplatin compared to control (44% vs. 2.3%), supporting that ALDH1A1 is a stem cell marker. A37 is a novel ALDH1A1 enzymatic inhibitor (Ki of 5nM). A37 decreased cell viability and spheroid formation by IGROV1 cells (p<0.001). A37 also decreased the percentage of ALDH+ cells under 3D culture conditions. These data support the role of β-catenin regulated ALDH1A1 in the maintenance of OC spheroids and of a stem cell phenotype and propose new ALDH1A1 inhibitors targeting this cell population. (Funding: US Department of Veterans Affairs and Ovarian Cancer Research Fund) Citation Format: Salvatore Condello, Sarbajeet Nagdas, Cynthia Morgan, John Turek, Thomas Hurley, Daniela Matei. Beta-catenin regulated ALDH1A1 is a target in ovarian cancer stem cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1309.