Oncotarget

Research Papers:

Coupling the modules of EMT and stemness: A tunable ‘stemness window’ model

Mohit Kumar Jolly _, Dongya Jia, Marcelo Boareto, Sendurai A. Mani, Kenneth J. Pienta, Eshel Ben-Jacob and Herbert Levine

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Oncotarget. 2015; 6:25161-25174. https://doi.org/10.18632/oncotarget.4629

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Abstract

Mohit Kumar Jolly1,3,*, Dongya Jia1,2,*, Marcelo Boareto1,7, Sendurai A. Mani8, Kenneth J. Pienta9,10,11,12, Eshel Ben-Jacob1,5,6,†, Herbert Levine1,3,4,5

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 Translational Molecular Pathology, and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

9The James Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

10Departments of Urology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

11Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

12Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA

*These authors have contributed equally to this work

†Deceased on June 5, 2015

Correspondence to:

Herbert Levine, e-mail: [email protected]

Keywords: partial EMT, stemness window, cancer stem cells, OVOL, multistability

Received: June 02, 2015     Accepted: July 10, 2015     Published: July 23, 2015

ABSTRACT

Metastasis of carcinoma involves migration of tumor cells to distant organs and initiate secondary tumors. Migration requires a complete or partial Epithelial-to-Mesenchymal Transition (EMT), and tumor-initiation requires cells possessing stemness. Epithelial cells (E) undergoing a complete EMT to become mesenchymal (M) have been suggested to be more likely to possess stemness. However, recent studies suggest that stemness can also be associated with cells undergoing a partial EMT (hybrid E/M phenotype). Therefore, the correlation between EMT and stemness remains elusive. Here, using a theoretical framework that couples the core EMT and stemness modules (miR-200/ZEB and LIN28/let-7), we demonstrate that the positioning of ‘stemness window’ on the ‘EMT axis’ need not be universal; rather it can be fine-tuned. Particularly, we present OVOL as an example of a modulating factor that, due to its coupling with miR-200/ZEB/LIN28/let-7 circuit, fine-tunes the EMT-stemness interplay. Coupling OVOL can inhibit the stemness likelihood of M and elevate that of the hybrid E/M (partial EMT) phenotype, thereby pulling the ‘stemness window’ away from the M end of ‘EMT axis’. Our results unify various apparently contradictory experimental findings regarding the interconnection between EMT and stemness, corroborate the emerging notion that partial EMT associates with stemness, and offer new testable predictions.


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