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Matrix Biol. 2017 Jul;60-61:157-175. doi: 10.1016/j.matbio.2017.01.001. Epub 2017 Jan 19.

Fibronectin fibrils regulate TGF-β1-induced Epithelial-Mesenchymal Transition.

Author information

1
Department of Biomedical Engineering, Virginia Commonwealth University, 800 E. Leigh St., Richmond, VA 23298, United States. Electronic address: griggsla@vcu.edu.
2
Department of Biomedical Engineering, Virginia Commonwealth University, 800 E. Leigh St., Richmond, VA 23298, United States. Electronic address: hassannt@vcu.edu.
3
Department of Biomedical Engineering, Virginia Commonwealth University, 800 E. Leigh St., Richmond, VA 23298, United States. Electronic address: rmalik@vcu.edu.
4
Department of Biomedical Engineering, Virginia Commonwealth University, 800 E. Leigh St., Richmond, VA 23298, United States. Electronic address: griffinbp@vcu.edu.
5
Department of Biomedical Engineering, Virginia Commonwealth University, 800 E. Leigh St., Richmond, VA 23298, United States. Electronic address: martinezba@vcu.edu.
6
Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall St., Richmond, VA 23298, United States; Massey Cancer Center, Virginia Commonwealth University, 101 W Franklin St., Richmond, VA 23220, United States. Electronic address: lynne.elmore@vcuhealth.org.
7
Department of Biomedical Engineering, Virginia Commonwealth University, 800 E. Leigh St., Richmond, VA 23298, United States; Massey Cancer Center, Virginia Commonwealth University, 101 W Franklin St., Richmond, VA 23220, United States. Electronic address: clemmon@vcu.edu.

Abstract

Epithelial-Mesenchymal Transition (EMT) is a dynamic process through which epithelial cells transdifferentiate from an epithelial phenotype into a mesenchymal phenotype. Previous studies have demonstrated that both mechanical signaling and soluble growth factor signaling facilitate this process. One possible point of integration for mechanical and growth factor signaling is the extracellular matrix. Here we investigate the role of the extracellular matrix (ECM) protein fibronectin (FN) in this process. We demonstrate that inhibition of FN fibrillogenesis blocks activation of the Transforming Growth Factor-Beta (TGF-β) signaling pathway via Smad2 signaling, decreases cell migration and ultimately leads to inhibition of EMT. Results show that soluble FN, FN fibrils, or increased contractile forces are insufficient to independently induce EMT. We further demonstrate that inhibition of latent TGF-β1 binding to FN fibrils via either a monoclonal blocking antibody against the growth factor binding domain of FN or through use of a FN deletion mutant that lacks the growth factor binding domains of FN blocks EMT progression, indicating a novel role for FN in EMT in which the assembly of FN fibrils serves to localize TGF-β1 signaling to drive EMT.

KEYWORDS:

Epithelial-Mesenchymal Transition; Extracellular matrix; Fibronectin; TGF-β1

PMID:
28109697
PMCID:
PMC5438896
DOI:
10.1016/j.matbio.2017.01.001
[Indexed for MEDLINE]
Free PMC Article

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