title: Coupling the modules of EMT and stemness: A tunable 'stemness window' model.
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.
authors: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA.|Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA.
authors: Mohit Kumar
authors: MK
authors: Jolly
authors: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA.|Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX 77005-1827, USA.
authors: Dongya
authors: D
authors: Jia
authors: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA.|Institute of Physics, University of Sao Paulo, Sao Paulo 05508, Brazil.
authors: Marcelo
authors: M
authors: Boareto
authors: Department of Translational Molecular Pathology, and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Sendurai A
authors: SA
authors: Mani
authors: The James Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.|Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.|Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors: Kenneth J
authors: KJ
authors: Pienta
authors: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA.|Department of Biosciences, Rice University, Houston, TX 77005-1827, USA.|School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors: Eshel
authors: E
authors: Ben-Jacob
authors: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA.|Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA.|Department of Physics and Astronomy, Rice University, Houston, TX 77005-1827, USA.|Department of Biosciences, Rice University, Houston, TX 77005-1827, USA.
authors: Herbert
authors: H
authors: Levine
mesh_terms: D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C000715187:Lin28A protein, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C487931:mirnlet7 microRNA, human
keywords: OVOL; cancer stem cells; multistability; partial EMT; stemness window