title: Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2.
abstract: Phenotypic plasticity involves a process in which cells transiently acquire phenotypic traits of another lineage. Two commonly studied types of phenotypic plasticity are epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). In carcinomas, EMT drives invasion and metastatic dissemination, while MET is proposed to play a role in metastatic colonization. Phenotypic plasticity in sarcomas is not well studied; however, there is evidence that a subset of sarcomas undergo an MET-like phenomenon. While the exact mechanisms by which these transitions occur remain largely unknown, it is likely that some of the same master regulators that drive EMT and MET in carcinomas also act in sarcomas. In this study, we combined mathematical models with bench experiments to identify a core regulatory circuit that controls MET in sarcomas. This circuit comprises the microRNA 200 (miR-200) family, ZEB1, and GRHL2. Interestingly, combined expression of miR-200s and GRHL2 further upregulates epithelial genes to induce MET. This effect is phenocopied by downregulation of either ZEB1 or the ZEB1 cofactor, BRG1. In addition, an MET gene expression signature is prognostic for improved overall survival in sarcoma patients. Together, our results suggest that a miR-200, ZEB1, GRHL2 gene regulatory network may drive sarcoma cells to a more epithelial-like state and that this likely has prognostic relevance.
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA jason.somarelli@duke.edu.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Somarelli
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Shetler
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas, USA Department of Bioengineering, Rice University, Houston, Texas, USA.
authors.forename: Mohit K
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Xueyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Bartholf Dewitt
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Hish
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Shivee
authors.initials: S
authors.lastname: Gilja
authors.affiliation: Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Eward
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Ware
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, Texas, USA Department of Bioengineering, Rice University, Houston, Texas, USA.
authors.forename: Herbert
authors.initials: H
authors.lastname: Levine
authors.affiliation: Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Solid Tumor Program and Duke Prostate Center, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Program in Molecular Genetics and Genomics, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Garcia-Blanco
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008962:Models, Theoretical; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D012509:Sarcoma / Q000235:genetics / Q000473:pathology*; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics*
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