Mesenchymal Epithelial Transition

Mesenchymal Epithelial Transition (MET) is the active molecular and cell-biological process by which a mesenchymally transitioned tumor cell reverses its phenotype, re-establishing epithelial cell-cell junctions, apical-basal polarity, and epithelial gene expression while downregulating mesenchymal transcription factors and associated invasive machinery, functioning as the mechanistic reverse counterpart to EMT rather than a passive default state a cell returns to. Where EMT reversibility describes the general capacity and degree to which reversal is possible, MET specifically describes the defined molecular program executing that reversal, considered central to the successful colonization phase of metastasis following dissemination in a mesenchymal or partial-EMT state.

MET-Inducing Signals

MET is triggered by a distinct, and in several cases directly opposing, set of signals relative to those driving EMT:

1. Bone Morphogenetic Protein 7 (BMP7) — A TGF-β superfamily member that, despite structural relatedness to the classical EMT-inducing TGF-β ligands, activates a distinct SMAD1/5/8 signaling branch that promotes epithelial gene expression and has been directly shown to counteract TGF-β-induced EMT and drive reversion in several experimental systems.
2. Loss of Exogenous EMT-Inducing Signal Exposure — Simple removal from a microenvironmental niche rich in TGF-β, hepatocyte growth factor, or hypoxic conditions (such as occurs upon successful extravasation into a well-oxygenated, non-fibrotic distant organ parenchyma) removes the sustaining upstream input for signaling-level EMT maintenance, permitting reversion in cells that have not accumulated durable epigenetic locking.
3. Adhesive Substrate Availability — Encountering a basement membrane-rich, adhesion-permissive microenvironment at a distant metastatic site (in contrast to the degraded, remodeled matrix of the invasive primary tumor front) provides integrin engagement signals that favor re-establishment of stable, junction-competent epithelial architecture.
4. Re-expression of miR-200 Family MicroRNAs — Whether triggered by upstream signaling change or occurring through stochastic fluctuation within the ZEB1/miR-200 bistable circuit, increased miR-200 expression directly represses residual ZEB1/2 mRNA, tipping the regulatory circuit back toward its epithelial-favoring stable state.

Sequential Molecular Events of MET

MET proceeds through a sequence of events broadly mirroring, in reverse order, the sequence described for EMT initiation and execution:

1. Decline of EMT Transcription Factor Expression — Reduced upstream signaling and reduced autocrine reinforcement lead to declining Snai1, Zeb1, and Twist1 expression and activity, removing the repressive pressure on epithelial gene loci.
2. Re-expression of Epithelial Genes — E-cadherin, claudins, and other junctional and polarity genes are transcriptionally re-activated as EMT transcription factor-mediated repression is relieved, provided the relevant loci have not accumulated durable DNA methylation-based silencing.
3. Re-establishment of Cell-Cell Junctions — Newly synthesized E-cadherin traffics to the cell surface and re-establishes stable adherens junction contacts with neighboring cells, restoring cohesive multicellular architecture.
4. Re-establishment of Apical-Basal Polarity — Polarity complex proteins (Par, Crumbs, Scribble) relocalize to their characteristic apical and basolateral membrane domains, restoring the fixed spatial organization characteristic of stationary epithelium and dismantling the front-rear migratory polarity axis.
5. Cytoskeletal Reversion — The vimentin intermediate filament network is progressively replaced by re-expressed keratin filaments, and actin reorganizes from a stress-fiber and lamellipodia-dominated architecture back toward the cortical, junction-anchored organization of stationary epithelium.

Diagram: MET as the Reverse Molecular Sequence of EMT

Role in Metastatic Colonization

MET is considered a mechanistically important, though not universally obligatory, step supporting successful macrometastatic colonization: proliferative outgrowth into a clinically detectable secondary tumor generally requires re-establishment of stable, organized multicellular architecture, and disseminated cells that remain in a purely mesenchymal, migratory, and comparatively anti-proliferative state have reduced capacity to form organized colonies, consistent with the general observation that many established macrometastases display predominantly epithelial histology resembling the primary tumor, in support of the "EMT for dissemination, MET for colonization" model of the invasion-metastasis cascade, though it is understood that partial-EMT and hybrid states may bypass the need for a complete MET given their retained junctional capacity.

Incomplete and Partial MET

Like EMT itself, MET is not necessarily a complete, all-or-none reversal; cells may undergo only partial MET, re-establishing sufficient epithelial character to support proliferative colonization while retaining residual mesenchymal features (persistent vimentin expression, retained invasive gene expression capacity), potentially conferring latent invasive or dormancy-related properties even within an outwardly epithelial secondary tumor, and contributing to the phenotypic heterogeneity frequently observed within metastatic lesions.

Experimental Assessment

Mesenchymal epithelial transition is studied using in vivo lineage tracing models that permanently mark cells having undergone EMT, allowing direct identification of MET at metastatic sites by co-localizing the permanent EMT-history label with re-expressed epithelial markers, in vitro reversion assays applying BMP7 or removing sustaining signals to previously EMT-induced cells with time-course tracking of junctional and polarity marker re-establishment, and comparative histopathological analysis of matched primary tumor and metastatic lesion specimens to assess the degree of epithelial phenotype concordance as indirect evidence of MET having occurred during colonization.