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