**2. EMT: a naturally occurring transdifferentiation program**

Normal adult tissues in terminally differentiated cells have been reprogrammed into pluripo‐ tent stem cells in the past 10 years [1, 2]. This process has resulted in the wide acceptance of the initial hypothesis that nearly any type of dedifferentiation or transdifferentiation is possible if the ectopic expression of a transcription factor is properly combined into adult cells. The successful experiments on reprogramming have led to the exploration of the factors that change the state of cells in nature rather than forced to ectopic gene expression.

EMT is the most important cell biology program among naturally occurring transdifferentia‐ tion programs. This process converts epithelial cells into mesenchymal derivatives, which is the reverse process of mesenchymal-epithelial transformation (MET) [3]. Accumulated evidence for the past two decades has suggested that EMT occurs during development to ensure the interconversions of cells utilized in the formation of different types of cells, thereby forming the organs of organization and complex multicellular organisms [3, 4]. This cell biological program is orchestrated by a group of transcription factors (EMT-TFs), such as the Snail, Twist, and Zeb families [4, 5].

Two other aspects of EMT are worthy to be discussed in detail. The EMT program in some epithelial tissues is apparently correlated with the residence of cells in stem cell-like states. Moreover, versions of the EMT program are adopted by cancer cells to obtain a series of processes associated with higher levels of malignancy. EMT exhibits the presence of mechan‐ ical connections between an individual and the pathogenesis of cancer. These processes prior to EMT are insignificant.

EMT governs changes in cell states along the epithelial versus mesenchymal axes and converts epithelial cells to mesenchymal cells when this program is fully executed. Weinberg described the extreme poles of the epithelial versus mesenchymal axes. Epithelial cells, frequently with polygonal shapes in monolayer culture, are polarized along their apical-basal axis and are tightly connected with one another laterally via adherens and tight junctions in vivo. These lateral ties can ensure the structural integrity of epithelial cell sheets. By contrast, full mesen‐ chymal cells exhibit spindle-like morphology with no sign of apical-basal polarity. These cells are loosely attached to the surrounding extracellular matrix (ECM) through focal adhesions. These features can help improve motility and explain the invasion of mesenchymal cells relative to their epithelial counterparts.

The deep layer of biological contact between epithelial and mesenchymal cells is determined by the differences in their respective transcription programs. These programs also control the expression of other gene products and key structural proteins, including those involved in the maintenance of the cytoskeleton and the strengthening of cell-cell adhesion [3–5]. Thus, epithelial cells express different types of keratin to form intermediate filaments, whereas vimentin constitutes the intermediate filament protein of mesenchymal cells. The expression of cell adhesion molecules and polarized complexes in mesenchymal cells is generally inhibited. EMT is marked by the replacement of E-cadherin by N-cadherin, which leads to the formation of weak cell adhesion between adjacent cells.

EMT can be significantly and rapidly activated in epithelial cells in response to physiological signals in a cell autonomous or non-cell autonomous manner. When gastrulation is used as an example, EMT responds to the induction signal as follows. The program is activated in ectodermal epithelial cells and completely converts epithelial cells into mesoderm mesenchy‐ mal cells, such as fibroblast growth factor and Wnt signaling pathway [6]. Similarly, EMT can be rapidly activated in adult tissues; it reacts to wounding and promotes rapid wound healing. This process is necessary to reconstruct the epithelial barrier that is essential for protecting internal organs from external injury [7]. Such rapid conversion between epithelial and mesenchymal states suggests the plasticity of epithelial cells, which facilitates their response to EMT-inducing signals. In addition, this plasticity demonstrates that residence in one of these two states is maintained in a metastable manner, with complex molecular and cellular mechanisms to ensure that a cell is in one or another state for a long period.

The description of EMT as a binary that shifts cells from a fully epithelial state into a fully mesenchymal state misreads the normal actions of this program. EMT is typically only from a fully epithelial state to a partially mesenchymal state, with certain key epithelial markers retained [8, 9]. Nevertheless, obtaining even a subset of mesenchymal traits to endow cells that previously resided in a fully epithelial state with a suite of mesenchymal traits will produce far-reaching effect on their biology.
