OVOL guides the epithelial-hybrid-mesenchymal transition

// Dongya Jia 1, 2, * , Mohit Kumar Jolly 1, 3, * , Marcelo Boareto 1, 7 , Princy Parsana 8 , Steven M. Mooney 9, 10 , Kenneth J. Pienta 9, 10, 11, 12 , Herbert Levine 1, 3, 4 , Eshel Ben-Jacob 1, 5, 6 1 Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA 2 Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX 77005-1827, USA 3 Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA 4 Department of Physics and Astronomy, Rice University, Houston, TX 77005-1827, USA 5 Department of Biosciences, Rice University, Houston, TX 77005-1827, USA 6 School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel 7 Institute of Physics, University of Sao Paulo, Sao Paulo 05508, Brazil 8 Department of Computer Science, Johns Hopkins University, Baltimore, MD 21287, USA 9 The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 10 Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 11 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 12 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA * These authors have contributed equally to this work Correspondence to: Kenneth J. Pienta, e-mail: kpienta1@jhmi.edu Herbert Levine, e-mail: herbert.levine@rice.edu Eshel Ben-Jacob, e-mail: eshel@rice.edu Keywords: EMT, metastasis, OVOL, partial EMT, cancer systems biology Received: March 04, 2015 Accepted: April 10, 2015 Published: April 22, 2015 ABSTRACT Metastasis involves multiple cycles of Epithelial-to-Mesenchymal Transition (EMT) and its reverse-MET. Cells can also undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype that has maximum cellular plasticity and allows migration of Circulating Tumor Cells (CTCs) as a cluster. Hence, deciphering the molecular players helping to maintain the hybrid E/M phenotype may inform anti-metastasis strategies. Here, we devised a mechanism-based mathematical model to couple the transcription factor OVOL with the core EMT regulatory network miR-200/ZEB that acts as a three-way switch between the E, E/M and M phenotypes. We show that OVOL can modulate cellular plasticity in multiple ways - restricting EMT, driving MET, expanding the existence of the hybrid E/M phenotype and turning both EMT and MET into two-step processes. Our theoretical framework explains the differences between the observed effects of OVOL in breast and prostate cancer, and provides a platform for investigating additional signals during metastasis.