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Epithelialmesenchymal transition(EMT)is a reversible cellular programme that transiently places epithelial cells into quasi-mesenchymal cell states14.During this process,epithelial cells progressively lose their cobble-stone epithelial appearance in monolayer cultures to adopt a spindle-shaped,mesenchymal morphology.The resulting more-mesenchymal cells can revert back to an epithelial state in the reverse process,known as mesenchymalepithelial transition(MET)(FiG.1).EMT has important roles in specific steps of embryogenesis such as gastrulation,tissue morphogenesis during devel-opment and wound healing in the adult1,3,4.Moreover,the malignant progression of many types of carcinoma,quite possibly all of them,depends on EMT activation in neoplastic cells57.During the course of tumour pro-gression,this pleiotropic programme confers on indi-vidual carcinoma cells multiple traits associated with high-grade malignancy610.Normally,the cells that form epithelial sheets in vari-ous tissues of the body display apicalbasal polarity and are held together laterally by tight junctions and adherens junctions,the latter of which are formed by cell surface epithelial cadherin(E-cadherin)molecules.This organization is crucial for the structural integrity of epithelia.Upon activation of EMT,E-cadherin expres-sion is repressed,which leads to the loss of the typical polygonal,cobblestone morphology of epithelial cells.The cells acquire a spindle-shaped mesenchymal mor-phology and express markers that are associated with the mesenchymal cell state,notably neural cadherin(N-cadherin),vimentin and fibronectin3(FiG.1).EMT is orchestrated by EMT-inducing transcriptions factors(EMT-TFs),which act pleiotropically and in various combinations to induce the expression of genes that pro-mote the mesenchymal cell state and repress the expres-sion of genes that maintain the epithelial state14.Diverse lines of evidence indicate that EMT is orchestrated as an epigenetic process that is not dependent upon concomi-tant DNA sequence alterations in normal and neoplastic cells11.Hence,like many other biological programmes,the expression of this programme and its wide-ranging effects on tumour biology cannot be determined by sequencing cancer cell genomes.In the context of neoplasia,the EMT programme orchestrated by the EMT-TFs can impart several traits that are essential to the malignant progression of car-cinoma cells,including tumour-initiating properties,motility,the ability to disseminate and elevated resist-ance to killing by commonly employed chemotherapeu-tics810,12,13.The detection of many of the EMT-associated protein markers can be used by pathologists as highly specific indicators of high-grade malignancy14.EMT is very rarely activated as a cell-autonomous process in carcinoma cells.Signals deriving from the tumour-associated reactive stroma act on carcinoma cells to induce the expression of EMT-TFs,which in turn orchestrate the expression of various components of the EMT programme.The stroma associated with High-grade malignancyA poorly differentiated cancer that is typically associated with poor prognosis and reduced overall survival.New insights into the mechanisms of epithelialmesenchymal transition and implications for cancerAnushkaDongre1 and RobertA.Weinberg1,2,3*Abstract|Epithelialmesenchymal transition(EMT)is a cellular programme that is known to becrucial for embryogenesis,wound healing and malignant progression.During EMT,cellcell and cellextracellular matrix interactions are remodelled,which leads to the detachment of epithelial cells from each other and the underlying basement membrane,and a new transcriptional programme is activated to promote the mesenchymal fate.In the context of neoplasias,EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens.In this Review,we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues,and the cell-intrinsic signals that sustain expression of this programme.We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state,which could function as cancer stem cells.In addition,we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas.1Whitehead Institute for Biomedical Research,Cambridge,MA,USA.2MIT Ludwig Center for Molecular Oncology,Cambridge,MA,USA.3Department of Biology,Massachusetts Institute of Technology,Cambridge,MA,USA.*e-mail:weinberg wi.mit.eduhttps:/doi.org/10.1038/s41580-018-0080-4REviEwsNature reviews|Molecular cell Biologyhigh-grade carcinomas resembles in many respects the stroma of normal epithelial tissues during inflamma-tion and wound healing.Tumour-associated macro-phages and fibroblasts within the stroma employ juxtacrine signalling and paracrine signalling channels to induce EMT in various types of nearby carcinoma cell1517.Acting reciprocally,carcinoma cells expressing EMT-associated markers can modulate the activities of various cellular components of the stroma that together form the tumour microenvironment18.Recent studies have indicated that cells undergoing EMT are also able to regulate antitumour immunity.Specifically,mesenchymal carcinoma cells exhibit increased resistance to elimination by cells of the adaptive immune system,many of which are present in the tumour-associated stroma18,19.Hence,the EMT and the quasi-mesenchymal state that it induces have important implications for clinical oncology,as they impart elevated resistance to both chemotherapy and immunotherapy.Furthermore,the ability of mesen-chymal carcinoma cells to mount resistance to sev-eral treatment regimens explains why characterizing EMT programmes has become crucial to understand carcinoma cellbiology.In this Review,we discuss recent advances in under-standing the activation and progression of EMT in normal and neoplastic tissues.We also describe the bidirec-tional crosstalk operating within individual tumours between the stromal microenvironment and carcinoma cells undergoing EMT and the implications of these new findings on the efficacy of therapeutic regimens.EMT and the actions of EMT-TFsEMT programmes have been classified into three types depending on the biological context in which they occur3.Type I EMT is observed during embryonic devel-opment,type II EMT occurs during wound healing and tissue regeneration,and type III EMT occurs during carcinoma progression.It remains to be seen whether these classes of EMT programme are truly distinct from one another or whether they are different manifestations of a common cellular process.Although we often refer here to a single EMT programme,many variations of this programme can operate in various normal tissues and neoplastic growths depending on which EMT-TFs are expressed,the nature of differentiation programmes that affected cells were committed to and even the mix of afferent signals that originate from their micro-environment,which perturb the behaviour of epithelial carcinoma cells and induce expression of EMT-TFs in various combinations.Cellular changes during EMT.Epithelial cells are nor-mally held together by lateral cellcell junctions(tight junctions,adherens junctions,gap junctions and desmo-somes).They exhibit apicalbasal polarity and interact with the underlying basement membrane via hemi-desmosomes and 64 integrins.Additionally,epithelial cells express specific cytokeratins that stabilize desmo-somes to ensure the resilience of epithelial cell layers to various physical stresses12,20.Normal and neoplastic epithelial cells that have activated an EMT programme very rarely advance to a fully mesenchymal state.They usually proceed to a partially epithelial and partially mesenchymal state in which they express a mixture of markers.Hence,EMT is often depicted as cells entering various discrete cell states arrayed along the epithelialmesenchymal spectrum of phenotypes.In spite of these variable manifestations in normal and neoplastic cell types,for simplicity,we depict it here as a single programme.Activation of EMT results in the loss of cell polar-ity,disruption of cellcell junctions,degradation of the underlying basement membrane and reorganization of the extracellular matrix(ECM)(FiG.1).The resulting quasi-mesenchymal cells display frontrear polarity ApicalBasalFrontBackTightjunctionAdherensjunctionDesmosomeEpithelialPartialMesenchymalHemidesmosomeBasementmembraneEMT Crumbs PATJ LGL E-cadherin Epithelial cell adhesionmolecule Occludins Claudins 64 integrins Cytokeratins N-cadherin Vimentin Fibronectin 1 and 3 integrins MMPs ZEB family SNAIL and/or SLUG TWIST1Repression ofepithelial stateInduction ofmesenchymal stateActinstress fibresMETFig.1|outline of a typical eMT programme.Epithelial cells displaying apicalbasal polarity are held together by tight junctions,adherens junctions and desmosomes and are tethered to the underlying basement membrane by hemidesmosomes.These cells express molecules that are associated with the epithelial state and help maintain cell polarity(listed in the yellow and light orange boxes,respectively).Induction of epithelialmesenchymal transition(EMT)leads to the expression of the EMT-inducing transcription factors(EMT-TFs)ZEB,SNAIL and TWIST,which inhibit the expression of genes associated with the epithelial state(listed in the yellow box)and concomitantly activate the expression of genes associated with the mesenchymal state(listed in the dark orange box).These changes in gene expression result in cellular changes that include the disassembly of epithelial cellcell junctions and the dissolution of apicalbasal cell polarity via repression of crumbs,PALS1-associated tight junction protein(PATJ)and lethal giant larvae(LGL),which are proteins that specifically regulate tight junction formation and apicalbasal polarity.This progressive loss of epithelial features is accompanied by acquisition of a partial set of mesenchymal features with retention of certain epithelial features;in certain circumstances,a complete set of mesenchymal features may be acquired.Mesenchymal cells display front-to-back polarity and an extensively reorganized cytoskeleton and express a distinct set of molecules and EMT-TFs that promote and maintain the mesenchymal state.During EMT,cells become motile and acquire invasive capacities.EMT is a reversible process,and mesenchymal cells can revert to the epithelial state by undergoing mesenchymalepithelial transition(MET).EMT and MET occur during normal development and during cancer progression.Itshould be noted,however,that carcinoma cells in spontaneously arising tumours only very rarely advance into a completely mesenchymal state.E-cadherin,epithelial cadherin;MMP,matrix metalloproteinase;N-cadherin,neural cadherin.Juxtacrine signallingA type of signalling that requires close contact between the interacting cell types.This type of signalling is also called contact-dependent signalling.Paracrine signallingA type of signalling that occurs via the exchange of chemical messengers such as cytokines,chemokines or ligands between the interacting cell types over somewhat short extensively reorganize the actin stress fibres that form an important component of their cytoskeleton12,20.Expression of E-cadherin and certain cytokeratins is lost,while expression of markers associated with the mesenchymal state is activated.Prominent among these are N-cadherin,vimentin,fibronectin and 1 and 3 integrins12,20.Degradation of the basement mem-brane facilitates cell invasion into the adjacent stroma and,in the case of carcinoma cells,dissemin ation to distant tissues4,20.As the EMT programme does not operate as a binary switch between epithelial and mes-enchymal states,carcinoma cells rarely execute a com-plete EMT programme that drives them into a fully mesenchymal state2,21,22.The EMT-TFs that have major roles in orchestrat-ing EMT programmes include the zinc-finger E-box-binding homeobox factors ZEB1 and ZEB2,SNAIL(also known as SNAI1),SLUG(also known as SNAI2)and the basic helixloophelix factors TWIST1 and TWIST2.These EMT-TFs regulate the expression of one another,and in different combinations,they induce the expression of hundreds of genes associated with the mesenchymal state and repress genes asso-ciated with the epithelial state.SNAIL represses the E-cadherin-encoding gene,CDH1,by binding to E boxes in the CDH1 promoter and recruiting the polycomb repressive complex2325.Similarly,ZEB1 transcription-ally represses CDH1 and induces the expression of the genes encoding vimentin and N-cadherin via recruit-ment of other chromatin modifiers to their promot-ers26,27.EMT-TFs also directly control the expression of several genes associated with cell polarity.SNAIL and ZEB1 transcriptionallyrepressthe expression of crumbs(a transmembrane protein),PALS1-associated tight junction protein(PATJ)(a scaffolding protein)and lethal giant larvae(LGL)(acytoskeletal protein),all of which are important for regulating tight junction forma-tion and apicalbasal polarity28,29.Additionally,SNAIL and ZEB2 activate the expression of matrix metallo-proteinases(MMPs)that facilitate the degradation of the basement membrane,promoting cell invasion30,31EMT during development and wound healing.The concept of EMT was first described by Greenberg and Hay,who demonstrated that the microenvironment experienced by cells in cultured epithelial tissues can exert profound effects on the morphology and migra-tory abilities of the epithelial cells32.The first evidence of EMT invivo came from the chicken embryo,where activation of an EMT programme was essential for regu-lating the formation of the mesoderm during gastrula-tion and the migration of cells that form the neural crest from the neural tube33.Subsequent studies highlighted the contributions of EMT to the regulation of various specific morphogenetic events during development.During gastrulation,EMT promotes the generation of mesenchymal cells of the incipient mesoderm from the epiblast3436.Additionally,the EMT is activated in neural crest cells and increases their migratory ability,enabling their dispersion to multiple sites throughout the body of the developing chordate embryo3739.EMT-TFs,espe-cially the two members of the SNAIL family,have crucial roles in developing embryos40.As an example,SNAIL and SLUG repress E-cadherin expression in the devel-oping mouse embryo,facilitating palatal fusion as well as the development of the neural crest41,42.In the adult,EMT programmes are important for tissue regeneration and repair observed during wound healing.During these processes,otherwise non-motile epithelial cells undergo EMT in order to migrate across a wound site,proliferate and then revert to the epithelial state to restore the integrity of the epithelial barrier as part of a process known as re-epithelialization43,44.The