title: OVOL guides the epithelial-hybrid-mesenchymal transition.
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.
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.|Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX 77005, USA.
authors.forename: Dongya
authors.initials: D
authors.lastname: Jia
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.|Department of Bioengineering, Rice University, Houston, TX 77005, USA.
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.|Institute of Physics, University of Sao Paulo, Sao Paulo 05508, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Boareto
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Princy
authors.initials: P
authors.lastname: Parsana
authors.affiliation: The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Mooney
authors.affiliation: The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.|Department of Bioengineering, Rice University, Houston, TX 77005, USA.|Department of Physics and Astronomy, Rice University, Houston, TX 77005, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Levine
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.|Department of Biosciences, Rice University, Houston, TX 77005, USA.|School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008962:Models, Theoretical; D009362:Neoplasm Metastasis / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology*; D049490:Systems Biology / Q000379:methods; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C490319:OVOL1 protein, human; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: EMT; OVOL; cancer systems biology; metastasis; partial EMT