Abstract
Epithelial-to-mesenchymal transition (EMT) programs contribute to the acquisition of invasive properties that are essential for metastasis. It is well established that EMT programs alter cell state and promote invasive behavior. This review discusses how rather than following one specific program, EMT states are diverse in their regulation and invasive properties. Analysis across a spectrum of models using a combination of approaches has revealed how unique features of distinct EMT programs dictate whether tumor cells invade as single cells or collectively as cohesive groups of cells. It has also been shown that the mode of collective invasion is determined by the nature of the EMT, with cells in a trailblazer-type EMT state being capable of initiating collective invasion, whereas cells that have undergone an opportunist-type EMT are dependent on extrinsic factors to invade. In addition to altering cell intrinsic properties, EMT programs can influence invasion through non-cell autonomous mechanisms. Analysis of tumor subpopulations has demonstrated how EMT-induced cells can drive the invasion of sibling epithelial populations through paracrine signaling and remodeling of the microenvironment. Importantly, the variation in invasive properties controlled by EMT programs influences the kinetics and location of metastasis.
Highlights
The acquisition of invasive ability (Figure 1) is an essential first step towards the development of metastatic cancer [1]
Advances made in unravelling the regulation of Epithelial-to-mesenchymal transition (EMT) that contribute to tissue development and inflammatory responses have established a signaling framework that has been used to reveal that EMTs contribute to tumor invasion and metastasis [10]
Extensive investigation using an array of tumor models supported by patient tumor analysis has demonstrated that EMT programs contribute to tumor invasion and metastasis
Summary
The acquisition of invasive ability (Figure 1) is an essential first step towards the development of metastatic cancer [1]. The EMT process involves a loss of polarity, a disruption of cell–cell adhesion, and the acquisition of migratory ability [7] These changes in cell state are coordinated by a combination of secondary modifications to existing proteins and alterations to cell signaling pathways through transcriptional and post-transcriptional changes that alter the pattern of gene expression [8]. Advances made in unravelling the regulation of EMTs that contribute to tissue development and inflammatory responses have established a signaling framework that has been used to reveal that EMTs contribute to tumor invasion and metastasis [10]. Suppression of Epithelial Traits The most established mechanism by which EMT programs promote cell migration is the suppression of the cell–cell adhesion protein E-cadherin. Slug, Zeb, and Zeb directly bind E-Box recognition sites in the E-cadherin
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