Epithelial-mesenchymal transitions: insights from development

Jormay Lim 1 Jean Paul Thiery () 0 1 2 0 Cancer Science Institute, National University of Singapore , 14 Medical Drive, 117599 , Singapore 1 Institute of Molecular Cell Biology , A 2 STAR , 61 Biopolis Drive, 138673 , Singapore T N E M P O L E V E D - Summary Epithelial-mesenchymal transition (EMT) is a crucial, evolutionarily conserved process that occurs during development and is essential for shaping embryos. Also implicated in cancer, this morphological transition is executed through multiple mechanisms in different contexts, and studies suggest that the molecular programs governing EMT, albeit still enigmatic, are embedded within developmental programs that regulate specification and differentiation. As we review here, knowledge garnered from studies of EMT during gastrulation, neural crest delamination and heart formation have furthered our understanding of tumor progression and metastasis. Introduction Epithelial-mesenchymal transition (EMT) is an evolutionarily conserved developmental process that contributes to the formation of the body plan, histogenesis and organogenesis. In the late 19th century, mesenchymal and epithelial cells were recognized as having distinct phenotypes (Duval, 1879) and, although EMT was apparent to embryologists (Platt, 1894), it only became interesting to developmental biologists in the 1960s. Following pioneering work from Elizabeth Hay (Greenburg and Hay, 1982; Hay, 2005), we now know that epithelial cells lose apicobasal polarity and intercellular junctions during EMT. These changes in cell polarity and adhesion disrupt the epithelial basement membrane and allow cellular penetration into an extracellular matrix (ECM)-rich compartment: a process referred to as delamination (see Glossary, Box 1). These newly formed mesenchymal cells transiently express distinct mesenchymal markers, acquire a front-rear polarity and become invasive, favoring cell-ECM rather than cell-cell adhesions. Interestingly, EMT is not irreversible: cells frequently cycle between epithelial and mesenchymal states via EMT and the reverse process, mesenchymal-epithelial transition (MET). Importantly, EMT has been implicated in pathological conditions, such as organ fibrosis, and in cancer, where it contributes to tumor progression and metastasis (Kalluri and Weinberg, 2009; Thiery et al., 2009). As such, much effort has been devoted to understanding the molecular regulation of EMT during development as an insight into the role and regulation of EMT in pathology. EMT is context dependent, occurring within the framework of other signaling mechanisms, such as cell fate induction, commitment and differentiation. However, the precise events that drive EMT are not fully understood. Genetic studies in Drosophila originally identified the transcription factors Twist and Snail as potential drivers of EMT during gastrulation (Leptin and Grunewald, 1990). Soon after, a Snail ortholog, Slug (Snai2), was shown to be involved in EMT in chicken embryo gastrulation (Nieto et al., 1994). Since then, several genes encoding transcription factors, cell polarity proteins and effector proteins have been shown to govern EMT in normal and transformed epithelial cells (see Table 1), suggesting that novel mechanisms govern EMT (Peinado et al., 2007; Moustakas and Heldin, 2009; Thiery et al., 2009; Nieto, 2011; Valastyan and Weinberg, 2011). In this Primer (see Box, Development: the big picture), we explore the molecular programs that govern EMT in various developmental contexts and discuss how these developmental studies have provided clues into to the control and activation of EMT during cancer. EMT during development Four waves of EMT and MET have been described during morphogenesis and organogenesis (see Table 2 for a summary of these different events during development). In mammals, for example, EMT occurs following implantation in the primitive endoderm to form the parietal endoderm (Veltmaat et al., 2000). Subsequently, during implantation, trophoblasts localized at the tip of chorionic villi undergo EMT and invade the endometrium (Kokkinos et al., 2010). EMT, and the reverse process MET, then occur at various stages throughout embryonic development, but we shall focus on the stages of gastrulation, neural crest delamination and heart formation, as they represent three distinct mechanisms of development that are associated with EMT. Gastrulation: formation of mesoderm and mesendoderm Different morphogenetic movements during gastrulation (see Glossary, Box 1) apply to different species. Even in the most ancient of species, such as cnidarians, there are no fewer than nine different mechanisms operating during gastrulation (Byrum and Martindale, 2004). In all cases, these complex morphogenetic movements incorporate epithelial cell plasticity, such as when cells invaginate or involute (see Glossary, Box 1) as cell collectives. Interestingly, in the early stages of body plan formation, cells participating in collective migration exchange neighbors through convergence-extension movements (Keller and Shook, 2004). EMT is one of the mechanisms activated during gastrulation that allows cells to ingress (see Glossary, Box 1) into a defined region of the embryo (the primitive streak in amniotes, the vegetal pole in sea urchin and the ventral furrow in Drosophila; see Glossary, Box 1) Development: the big picture This Primer is part of a series entitled Development: the big picture. This series aims to highlight key developmental systems or processes that have been the subject of intense study because they have broad implications for other developmental, cell and molecular systems, or for disease and therapeutics. Keep an eye out for other articles in this series over the coming months! Box 1. Glossary Delamination. The process whereby cells separate from an epithelial layer. Endocardial cushion. A structure formed by endocardial cells that undergo epithelial-mesenchymal transition (EMT) in an hyaluronic acid-rich extracellular matrix region named cardiac jelly. Epicardium. The outer cell layer of the heart primordium derived from the pro-epicardium, a cluster of cells proximal to the heart and liver. Gastrulation. The embryonic stage corresponding to the formation of the three primary germ layers: ectoderm, mesoderm and endoderm. Gastrulation involves either collective cell migration through invagination or involution (partial EMT), or individual cell migration by ingression (EMT). Heart primordium. A group of mesodermal cells specified for heart development during gastrulation. These cells assemble into two cardiogenic mesodermal layers, which later migrate anteriorly and fuse into a single heart tube. Ingression. A process that allows single cells to delaminate and migrate into the sub-epiblast territory; it is typical of EMT. Invagination. The process that drives an epithelium to fold inwards or outwards through the coordinated constriction of the apex of cells. Involut (...truncated)