A novel mechanism of plasminogen activation in epithelial and mesenchymal cells

Moamen Bydoun,David M Waisman,Andra Sterea,Ian C G Weaver,Alamelu G Bharadwaj

doi:10.1038/s41598-018-32433-y

Moamen Bydoun, David M Waisman + Show 3 more

Open Access

https://doi.org/10.1038/s41598-018-32433-y

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Abstract

Cancer dissemination is initiated by the movement of cells into the vasculature which has been reported to be triggered by EMT (epithelial to mesenchymal transition). Cellular dissemination also requires proteases that remodel the extracellular matrix. The protease, plasmin is a prominent player in matrix remodeling and invasion. Despite the contribution of both EMT and the plasminogen activation (PA) system to cell dissemination, these processes have never been functionally linked. We reveal that canonical Smad-dependent TGFβ1 signaling and FOXC2-mediated PI3K signaling in cells undergoing EMT reciprocally modulate plasminogen activation partly by regulating the plasminogen receptor, S100A10 and the plasminogen activation inhibitor, PAI-1. Plasminogen activation and plasminogen-dependent invasion were more prominent in epithelial-like cells and were partly dictated by the expression of S100A10 and PAI-1.

Highlights

Cancer dissemination is initiated by the movement of cells into the vasculature which has been reported to be triggered by EMT
It is currently believed that EMT is involved in the early invasive escape of cancer cells from the primary tumor site whilst MET is associated with metastatic site seeding and repopulation[52,53]
Cells possess multiple plasminogen receptors[22] that contribute to plasminogen activation, We here reported that S100A10 was the only plasminogen receptor regulated by TGFβ1-induced EMT, suggesting that S100A10 is a key regulator of the plasminogen activation system during TGFβ1-induced EMT., The depletion of S100A10 in A549 cells resulted in marked decrease in plasminogen activation, which is likely justified by an adequate level of S100A10 expression at the cell surface

Summary

Introduction

Cancer dissemination is initiated by the movement of cells into the vasculature which has been reported to be triggered by EMT (epithelial to mesenchymal transition). To compare the regulation of plasminogen activation in epithelial and mesenchymal cells, we established three 2D in vitro cell models; TGFβ1-induced EMT and serum withdrawal-induced generation of epithelial-like BEAS-2B30,31, A54932,33 and MCF-734 cells. TGFβ1 treatment of serum-supplemented BEAS-2B cells, that are mesenchymal in morphology, upregulated S100A10 protein expression (Supplemental Fig. 2c).

Results

Conclusion