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

// Mohit Kumar Jolly 1, 3, * , Dongya Jia 1, 2, * , Marcelo Boareto 1, 7 , Sendurai A. Mani 8 , Kenneth J. Pienta 9, 10, 11, 12 , Eshel Ben-Jacob 1, 5, 6, † , Herbert Levine 1, 3, 4, 5 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 Translational Molecular Pathology, and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 9 The James Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA 10 Departments of Urology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA 11 Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA 12 Department 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: herbert.levine@rice.edu 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.