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Review
. 2021 Sep 15;40(18):e108647.
doi: 10.15252/embj.2021108647. Epub 2021 Aug 30.

Dynamic EMT: a multi-tool for tumor progression

Simone Brabletz  1 , Harald Schuhwerk  1 , Thomas Brabletz  1 , Marc P Stemmler  1
Affiliations
Review

Dynamic EMT: a multi-tool for tumor progression

Simone Brabletz et al. EMBO J. .

Abstract

The process of epithelial-mesenchymal transition (EMT) is fundamental for embryonic morphogenesis. Cells undergoing it lose epithelial characteristics and integrity, acquire mesenchymal features, and become motile. In cancer, this program is hijacked to confer essential changes in morphology and motility that fuel invasion. In addition, EMT is increasingly understood to orchestrate a large variety of complementary cancer features, such as tumor cell stemness, tumorigenicity, resistance to therapy and adaptation to changes in the microenvironment. In this review, we summarize recent findings related to these various classical and non-classical functions, and introduce EMT as a true tumorigenic multi-tool, involved in many aspects of cancer. We suggest that therapeutic targeting of the EMT process will-if acknowledging these complexities-be a possibility to concurrently interfere with tumor progression on many levels.

Keywords: EMT; MET; SLUG; SNAIL; TWIST; ZEB1; ZEB2; cancer; cell plasticity; hybrid EMT; invasion; metastasis; partial EMT; signaling pathways; tumor stemness.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. Classical EMT functions and cancer
(A) EMT frequently occurs at the invasive front of epithelial tumors, destroys the well‐defined epithelial structures, and allows the cancer cells to migrate, invade the tissue, and intravasate in blood or lymphatic vessels. Tumor cells on their way through the body can travel as mesenchymal single cells, as cell clusters exhibiting partial EMT or as more epithelial cell clusters headed by a mesenchymal leader cell. At the secondary site, the cells extravasate and colonize the distant organ, where MET allows the outgrowth to macrometastases. (B) EMT is induced mainly by a set of transcription factors (EMT‐TFs) like ZEB1, ZEB2, SNAIL, SLUG and TWIST that differ in protein structure, size, and individual functions. All of them are repressors of epithelial factors like E‐cadherin and activate mesenchymal markers like Vimentin, Fibronectin or N‐cadherin. Epithelial cells displaying apical–basal polarity are held together by tight junctions, adherens junctions, and desmosomes and are anchored to the underlying basement membrane by hemidesmosomes. They express three different polarity complexes that together with the junctional molecules maintain epithelial cell polarity. In the classical EMT, expression of EMT‐TFs leads to inhibition of major components of these epithelial structures and concomitantly activates the expression of genes associated with the mesenchymal state. Cells gain front–rear polarity, display actin stress fibers, become motile and acquire invasive capacities. Notably, tumor cells very rarely switch to a completely mesenchymal phenotype, but fluently convert between various intermediate states displaying certain mesenchymal features but keeping partial sets of epithelial characteristics. Further, EMT is a reversible process. Mesenchymal cells can revert to the epithelial state undergoing MET. An important role in the execution of MET is played by microRNAs of the miR‐200 and mir‐34 families that are regulated in double‐negative feedback loops with the EMT‐TFs ZEB1/2 and SNAIL, respectively, that serve to reinforce either the epithelial or the mesenchymal state.
Figure 2
Figure 2. Dynamic EMT as a multi‐tool for tumor progression
Overview summarizing the multiple oncogenic EMT functions in the course of tumor progression. The classical EMT functions allow cancer cell to migrate, invade, intra‐ and extravasate blood and lymphatic vessels. At the distant sites, MET enables the outgrowth of macrometastases. The non‐classical EMT traits support tumor initiation as well as metastatic colonization. Throughout the whole process of tumor progression, they help the cells to cope with changing conditions by metabolic reprogramming, enhanced survival via altered DNA repair and prevention of cell death, immune evasion and improved resistance to chemo‐ and radiotherapy. Importantly, EMT is not only supporting the cancer cells to handle changing environmental conditions, but is also induced by extracellular signals from, e.g., CAFs or immune cells in the microenvironment or by therapeutic approaches.
Figure 3
Figure 3. Cellular plasticity of tumor cells is governed by EMT and provided in a window of partial EMT
Dynamic induction of EMT and MET changes cellular phenotypes of carcinoma cells. Drug sensitivity, proliferation, and response to apoptosis signals are highest in more epithelial states, whereas drug efflux, invasion, and immune evasion are highest in more mesenchymal states. A hybrid EMT state provides maximal stemness, tumor initiation capacity, and ability to adapt to environmental changes. Note that in extreme epithelial and mesenchymal states, features like stemness, tumor initiation, and colonization are lost.
Figure 4
Figure 4. Signaling pathways and their crosstalk during EMT induction
(A) Canonical receptor tyrosine kinase pathways activated by EGF/EGFR, PDGF/PDGFR, HGF/c‐Met and others, Wnt, TGFβ, Notch, Hippo, and Cytokine signaling (e.g., IL6, TNFα) and their nuclear effectors are shown, which all promote expression of core EMT‐TFs. Activation of EMT‐TFs results in execution of the EMT program, exemplified by regulated CDH1 and VIM expression. EMT is promoted by crosstalk of signaling pathways on multiple levels already in the cytoplasm (not shown). (B) Examples of EMT gene regulation of individual pathways and input from other signal transduction pathways. Effects on direct gene activation and repression are shown by green arrows and red block connections, respectively. For details, see text.
Figure 5
Figure 5. Cell types in the tumor microenvironment and contribution to EMT
Cells of the hematopoietic lineage, fibroblasts and others contribute to the TME. Exemplified modes of action and cytokines secreted from individual cell types are depicted which promote EMT, migration, invasion, and intravasation of tumor cells into blood vessels. EMT induction and co‐migration can be induced by TAMs and specific lymphocyte/tumor cell crosstalk.
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