New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer

Abstract

Epithelial–mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell–cell and cell–extracellular 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.

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Fig. 1: Outline of a typical EMT programme.
Fig. 2: Signalling pathways that activate EMT.
Fig. 3: Activation of EMT by stromal constituents of the tumour microenvironment.
Fig. 4: EMT and modulation of the immune response.

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Acknowledgements

The authors thank T. Shibue and A. W. Lambert for critical reading of the manuscript. The authors thank R. Lee for helping with preparation of the figures. A.D. was supported by a postdoctoral fellowship from the Ludwig Fund for Cancer Research. R.A.W. is an American Cancer Society research professor and a Daniel K. Ludwig Foundation cancer research professor. The work of the authors has been supported by grants from the US National Institutes of Health (NIH) (P01 CA080111), Breast Cancer Research Foundation, Samuel Waxman Cancer Research Foundation, Breast Cancer Alliance and the Ludwig Center for Molecular Oncology.

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Glossary

High-grade malignancy

A poorly differentiated cancer that is typically associated with poor prognosis and reduced overall survival.

Juxtacrine signalling

A type of signalling that requires close contact between the interacting cell types. This type of signalling is also called contact-dependent signalling.

Paracrine signalling

A 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 distances.

Adaptive immune system

A branch of the immune response mounted by a subset of immune cells that can recognize specific antigens, subsequently leading to the formation of immunological memory.

Immunotherapy

A type of treatment regimen that uses the immune system to mount defensive responses to diseases such as cancer. Immunotherapies restore the effector function of cytotoxic CD8+ T cells, enabling them to eradicate foreign agents.

Cytokeratins

Epithelial cell-specific intermediate filaments that are involved in desmosome stabilization to ensure the resilience of epithelial cell layers to various physical stresses.

Actin stress fibres

Contractile bundles of actin found in non-muscle cells that play important roles in morphogenesis, cell adhesion and migration.

Neural crest

A transient embryonic structure that arises in the neural tube. Neural crest cells are migratory and can differentiate into several cell types.

Regulatory T cells

(Treg cells). A subset of T cells that regulate the immune response by maintaining tolerance to self-antigens. Treg cells suppress effector T cells and are crucial for preventing autoimmunity. They are prevalent in the tumour microenvironment of most cancers.

M2 macrophages

Alternatively activated macrophages documented to secrete immunosuppressive, angiogenic and chemotactic factors. They are anti-inflammatory and promote wound healing, tissue repair and carcinoma progression.

Immunological synapse

A cellular interface formed between an antigen-presenting cell and a target cell.

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Dongre, A., Weinberg, R.A. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 20, 69–84 (2019). https://doi.org/10.1038/s41580-018-0080-4

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