Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2.
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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.
Published Version (Please cite this version)10.1128/MCB.00373-16
Publication InfoArmstrong, Andrew John; Bartholf DeWitt, Suzanne; Eward, William Curtis; Garcia-Blanco, Mariano Agustin; Gilja, Shivee; Hish, A; ... Ware, Kathryn E (2016). Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2. Mol Cell Biol, 36(19). pp. 2503-2513. 10.1128/MCB.00373-16. Retrieved from http://hdl.handle.net/10161/13882.
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Professor of Medicine
1. Predictors of sensitivity and clinical efficacy of therapies in advanced prostate cancer 2. Novel designs of clinical trials and pharmacodynamic/translational studies in prostate, kidney, bladder cancer 3. Pre-operative models for drug development of novel agents in human testing in prostate cancer 4. Novel therapies and drug development for prostate, renal, bladder, and testicular cancer 5. Design of rational combination therapies in men with metastatic hormone-refra
Assistant Professor of Orthopaedic Surgery
I am an Orthopaedic Oncologist, with dual clinical degrees (MD and DVM). I treat complex sarcomas in people and animals. My laboratory studies comparative oncology - discoveries we can make about cancer by analyses across different species.
Adjunct Professor in the Molecular Genetics and Microbiology
Human and viral genes are complex genetic units of information that are tightly regulated. The laboratory studies three aspects of this regulation: the interface between synthesis of mammalian messenger RNAs and the processing events required to mature these transcripts, the alternative processing of these messenger RNAs to produce multiple proteins from one gene, and the regulation of gene expression in human pathogenic flaviviruses. In the great majority of human transcripts
Medical Instructor in the Department of Medicine
Alphabetical list of authors with Scholars@Duke profiles.