Epithelial ovarian cancer (EOC) is highly heterogeneous with five molecular subgroups, Epi-A, Epi-B, Mes, Stem-A and Stem-B, being identified. The mechanisms behind the clonal evolution and intertumoral molecular heterogeneity are not fully elucidated. Previously, we performed EOC profiling meta-analysis to identify epithelial-mesenchymal transition (EMT) as the crucial mechanism for molecular heterogeneity. Transcription factors SNAI1, SNAI2, ZEB1, ZEB1, TWIST1, and GRHL2 were identified as crucial regulators for the Mes subtype which has undergone EMT. Here, we utilized three in-vitro EOC cell lines, PEO1, OVCA420, and OVCA429, to model the EMT-driven clonal evolution by manipulating the expression levels of these EMT transcriptional regulators. We analysed the molecular subtypes of matched primary tumor versus peritoneal metastases. Six out of 11 pairs showed concordant molecular subtypes. We also analysed a dataset of matched primary tumor versus omental metastases. Four out of 9 pairs showed concordant molecular subtypes. Among the 10 pairs showing a shift of molecular subtypes, 5 out of 5 omental metastases were designated as Mes. The variation in the evolution of molecular heterogeneity can be explained by the differences in the EMT transcriptional cross-regulation of the in-vitro models. Manipulating EMT regulators in PEO1 did not induce any transcriptional cross-regulation with no molecular subtype switching observed. However, manipulating EMT regulators in OVCA420 and OVCA429 caused hierarchical transcriptional control and feedback loop regulation, respectively. The OVCA429 model showed molecular subtype switch from Epi-A to Mes. In conclusion, the heterogeneity caused by EMT-driven clonal evolution is the consequence of transcriptional feedback loops of EMT regulators.

Citation Format: Chung VY, Tan M, Tan TZ, Kuay KT, Ye J, Thiery JP & Huang RY. Epithelial-mesenchymal transition driven by transcriptional feedback loops contributes to intertumoral molecular heterogeneity in the metastasis and relapse of epithelial ovarian cancer [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 AS03.