Abstract 1430: Transcriptional regulatory loops among SNAI1, TWIST1, ZEB1, and ZEB2 defines the epithelial-mesenchymal transition (EMT) spectrum in epithelial ovarian cancer (EOC)

Abstract

Abstract Epithelial-mesenchymal transition (EMT) refers to a sequential phenotypic transformation process from epithelial to mesenchymal states, which is well defined in embryonic development. During cancer progression, cancer cells undergo EMT progressively loss epithelial characteristics and gain mesenchymal properties and are correlated with acquisition of increased capacity of metastasis and resistance to chemo- and immunotherapy. Although EMT is intensively studied in various types of cancers, its role in epithelial ovarian cancer (EOC), the most lethal gynaecological malignancy in the world, has yet to be elucidated. Previously, our group proposed the concept of an EMT Spectrum which encompasses the hybrid “intermediate” phenotype as well as the bona-fide epithelial and mesenchymal phenotypes. EOC cells harboring intermediate phenotypes showed distinct functional differences in in vitro aggressiveness. We hypothesize that EMT transcriptional drivers, SNAI1, TWIST1, ZEB1, and ZEB2, contribute to different biological consequences and show different hierarchy to induce step-wise phenotypic changes along the EMT Spectrum. EMT models were established by overexpressing classic EMT drivers in selected EOC cell lines with different EM phenotypes at different positions of EMT spectrum to test the intrinsic transcriptional regulation networks. Quantitative PCR (QPCR) was performed to examine the cross regulation among the EMT transcriptional drivers and their downstream targets. There was no cross regulation detected in the most epithelial cell line, PEO1, while a simple, repressive regulatory net was found in the OVCA420 cell line. The cell line with an intermediate phenotype, OVCA429, showed a complex double positive feedback loop among the EMT drivers. The divergence in the transcriptional regulatory loops correlated with the differences of in vitro EMT functions. These results indicate that there is a dynamic EMT transcriptional regulatory network to further define the EMT spectrum. In conclusion, this study demonstrates that cancer cells with an intermediate phenotype are more easily to be pushed along the EMT spectrum due to their ability to initiate a complex transcriptional feedback regulatory loop. Citation Format: Ming Tan, Vin Yee Chuang, Tuan Zea Tan, Jean Paul Thiery, Ruby Yun-Ju Huang. Transcriptional regulatory loops among SNAI1, TWIST1, ZEB1, and ZEB2 defines the epithelial-mesenchymal transition (EMT) spectrum in epithelial ovarian cancer (EOC). [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 1430. doi:10.1158/1538-7445.AM2015-1430