title: Stability of the hybrid epithelial/mesenchymal phenotype.
abstract: Epithelial-to-Mesenchymal Transition (EMT) and its reverse - Mesenchymal to Epithelial Transition (MET) - are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and 'metastable'. Here, we identify certain 'phenotypic stability factors' (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be 'metastable', and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression.
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.|Department of Bioengineering, Rice University, Houston, TX, USA.
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Satyendra C
authors.initials: SC
authors.lastname: Tripathi
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.|Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX, USA.
authors.forename: Dongya
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, ON, Canada.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Mooney
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Muge
authors.initials: M
authors.lastname: Celiktas
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Red and Charline McCombs Institute for The Early Detection and Treatment of Cancer, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.affiliation: The James Brady Urological Institute, and Departments of Urology, Oncology, Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.|Graduate Program in Systems, Synthetic and Physical Biology, Rice University, Houston, TX, USA.|School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.|Department of Bioengineering, Rice University, Houston, TX, USA.|Department of Physics and Astronomy, Rice University, Houston, TX, USA.|Department of Biosciences, Rice University, Houston, TX, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Levine
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C470830:GRHL2 protein, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: cancer stem cells; cell-fate decisions; epithelial-mesenchymal transition; multistability; partial EMT