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.

Department

Description

Provenance

Subjects

Citation

Published Version (Please cite this version)

10.1128/MCB.00373-16

Publication Info

Somarelli, Jason A, Samantha Shetler, Mohit K Jolly, Xueyang Wang, Suzanne Bartholf Dewitt, Alexander J Hish, Shivee Gilja, William C Eward, et al. (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 https://hdl.handle.net/10161/13882.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Somarelli

Jason Andrew Somarelli

Assistant Professor in Medicine
Bartholf DeWitt

Suzanne Bartholf DeWitt

Postdoctoral Associate
Eward

William Curtis Eward

Frank H. Bassett III, M. D. Associate 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.

Armstrong

Andrew John Armstrong

Professor of Medicine

I am a clinical and translational investigator focused on precision therapies and biomarkers in advanced prostate and other GU cancers.  I oversee a large research team of clinical and lab based investigators focused on improving patient outcomes, preventing metastatic disease, and understanding the biology of aggressive prostate cancer.  Some key themes:
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-refractory prostate cancer
6. Developing prognostic and predictive models for progression and survival in metastatic prostate cancer
7. Examining surrogate markers of mortality in metastatic prostate cancer
8. Clear cell and non-clear cell renal cell carcinoma: natural history, sensitivity to novel agents including mTOR and VEGF inhibition


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.