Research ArticleCell Biology

TGF-β–induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops

Sci. Signal.  30 Sep 2014:
Vol. 7, Issue 345, pp. ra91
DOI: 10.1126/scisignal.2005304

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Stepping Through the Transitions in Cell State

Cells can change their functional and morphological characteristics in response to changes in the environment. Epithelial cells can exhibit a type of plasticity called epithelial-to-mesenchymal transition (EMT), in which they transform from cells with tight contacts to neighboring cells and function as a barrier into motile cells that are not connected to their neighbors. This process is important during physiological processes, such as wound healing, and can also contribute to metastatic progression of cancer. Zhang et al. performed population and single-cell analysis of changes in the abundance of core regulators of EMT in a mammary epithelial cell line culture to test theoretical models by which EMT could occur. Their analysis confirmed that two sequential feedback loops, involving transcription factors and microRNAs, function as two cascading switches to control the discrete steps in EMT and identified the first step in this two-step process as the only readily reversible one for these cells.

Abstract

The process of epithelial-to-mesenchymal transition (EMT) is an essential type of cellular plasticity associated with a change from epithelial cells that function as a barrier consisting of a sheet of tightly connected cells to cells with properties of mesenchyme that are not attached to their neighbors and are highly motile. This phenotypic change occurs during development and also contributes to pathological processes, such as cancer progression. The molecular mechanisms controlling the switch between the fully epithelial and fully mesenchymal phenotypes and cells that have characteristics of both (partial EMT) are controversial, and multiple theoretical models have been proposed. To test these theoretical models, we systematically measured the changes in the abundance of proteins, mRNAs, and microRNAs (miRNAs) that represent the core regulators of EMT induced by transforming growth factor–β1 (TGF-β1) in the human breast epithelial cell line MCF10A at the population and single-cell levels. We provide experimental confirmation for a model of cascading switches in phenotypes associated with TGF-β1–induced EMT of MCF10A cells that involves two double-negative feedback loops: one between the transcription factor SNAIL1 and the miR-34 family and another between the transcription factor ZEB1 and the miR-200 family. Furthermore, our data showed that whereas the transition from epithelial to partial EMT was reversible for MCF10A cells, the transition from partial EMT to mesenchymal was mostly irreversible at high concentrations of TGF-β1.

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