Oncotarget

Research Papers:

OVOL guides the epithelial-hybrid-mesenchymal transition

Dongya Jia, Mohit Kumar Jolly, Marcelo Boareto, Princy Parsana, Steven M. Mooney, Kenneth J. Pienta, Herbert Levine _ and Eshel Ben-Jacob

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Oncotarget. 2015; 6:15436-15448. https://doi.org/10.18632/oncotarget.3623

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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: [email protected]

Herbert Levine, e-mail: [email protected]

Eshel Ben-Jacob, e-mail: [email protected]

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.


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