Abstract
Dongya Jia1,2,*, Mohit Kumar Jolly1,3,*, Marcelo Boareto1,7, Princy Parsana8, Steven M. Mooney9,10, Kenneth J. Pienta9,10,11,12, Herbert Levine1,3,4, Eshel Ben-Jacob1,5,6
1Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA
2Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX 77005-1827, USA
3Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA
4Department of Physics and Astronomy, Rice University, Houston, TX 77005-1827, USA
5Department of Biosciences, Rice University, Houston, TX 77005-1827, USA
6School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel
7Institute of Physics, University of Sao Paulo, Sao Paulo 05508, Brazil
8Department of Computer Science, Johns Hopkins University, Baltimore, MD 21287, USA
9The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
10Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
11Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
12Department 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.
