Abstract B2-24: OVOL: A brake on EMT, driver of MET and expander of the hybrid E/M phenotype

Abstract

Abstract Aberrant activation of Epithelial to Mesenchymal Transition (EMT) and its reverse MET is a hallmark of cancer metastasis. Also, the carcinoma cells can undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype, which can allow them to migrate collectively and form clusters of Circulating Tumor Cells (CTCs). These clusters can be up to 50 times more metastatic compared to cells that undergo complete EMT or individually migrating CTCs. Here, using experimental data and bioinformatics, we devised a dedicated model to study the role of transcription factor OVOL in regulating these bidirectional epithelial-hybrid-mesenchymal transitions. The new model incorporates the coupling between OVOL and miR-200/ZEB - the three-way EMT/MET decision-making switch that allows for three phenotypes (E, M and E/M). We found that OVOL operates as a brake holder of complete EMT and as an expander of the hybrid E/M phenotype (it extends the range of physiological parameters for which the cells can attain the hybrid E/M phenotype). Inhibition of OVOL, for example by Wg signaling, removes that brake and supports a complete EMT. Conversely, overexpression of OVOL, for example by BMP7/Smad4, leads to the reverse of EMT, i.e. MET. In addition, OVOL elevates the phenotypic plasticity of cells by turning both EMT and MET into a two-step process (E to E/M to M, and M to E/M to E). We show that depending on the context-specific coupling manner of OVOL with miR-200/ZEB, OVOL can shepherd cellular plasticity in multiple ways - by driving MET, by restricting EMT, and by expanding the existence of the hybrid E/M phenotype. In particular, we explain how the differences between the observed effects of OVOL in breast and prostate cancer are associated with the results of different miR-200/ZEB/OVOL couplings. Our computational framework can be tailored to include other signals such as p53, TGF-beta, inflammation and hypoxia that affect the cellular plasticity during metastasis, thus providing a platform to design novel anti-metastasis therapies. Citation Format: Dongya Jia, Mohit Kumar Jolly, Marcelo Boareto, Princy Parsana, Steven Mooney, Kenneth J. Pienta, Herbert Levine, Eshel Ben-Jacob. OVOL: A brake on EMT, driver of MET and expander of the hybrid E/M phenotype. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-24.