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Collective cell migration in morphogenesis, regeneration and cancer

Key Points

  • Collective cell migration is defined as the coordinated movement of multiple cells that retain cell–cell contacts while coordinating their actin dynamics and intracellular signalling.

  • Because the cells form a structural and functional unit, both active and passive cell translocation occur.

  • The movement of connected cells contributes to morphogenesis, wound healing and cancer invasion and each process underlies homologous but distinct molecular mechanisms of cell–cell interaction and pro-migratory extracellular signalling.

  • The concept of collective movement explains how the body forms and reshapes as well as how cancer cells destructively invade as a 'socially' organized mass.

Abstract

The collective migration of cells as a cohesive group is a hallmark of the tissue remodelling events that underlie embryonic morphogenesis, wound repair and cancer invasion. In such migration, cells move as sheets, strands, clusters or ducts rather than individually, and use similar actin- and myosin-mediated protrusions and guidance by extrinsic chemotactic and mechanical cues as used by single migratory cells. However, cadherin-based junctions between cells additionally maintain 'supracellular' properties, such as collective polarization, force generation, decision making and, eventually, complex tissue organization. Comparing different types of collective migration at the molecular and cellular level reveals a common mechanistic theme between developmental and cancer research.

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Figure 1: Types and variants of collective cell migration.
Figure 2: Molecular mechanisms of different forms of collective migration.
Figure 3: The lateral line primordium couples collective migration to differentiation.

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Acknowledgements

We thank O. Ilina and C. Rose for providing immunofluorescence and histological images. This work was supported by grants to P.F. from the Deutsche Krebshilfe (106950), Deutsche Forschungsgemeinschaft (FR 1155/8-2) and European Union (European Molecular Imaging Laboratories LSHC-CT-2004-503569).

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Glossary

Invasion

A hallmark of cancer, measured as cells breaking away from their origin through the basement membrane. We use this term to mean all forms of cell movement through three-dimensional tissue that involve a change in tissue structure and, eventually, tissue destruction.

Basement membrane

A sheet-like layer of interwoven macromolecules, including laminin, collagen IV and link proteins, that structurally anchor an epithelium or endothelium to the adjacent interstitial tissue. Epithelial or endothelial cells and stromal cells cooperate and deposit the macromolecules from either side.

Border cell

One of a small cluster of cells that delaminate from the follicular epithelium of the Drosophila melanogaster egg chamber and migrate in a stereotypical pattern towards the developing oocyte. Ablation studies suggest that the function of border cells is to generate the micropyle, a structure at the dorso-anterior side of the oocyte that allows sperm entry.

Neural crest

A population of migrating, pluripotent cells that appears transiently in the dorsal neuroectoderm. In the chick embryo, neural crest cells move as loosely associated strands or streams throughout the entire embryo and give rise to different tissues, including craniofacial bones and cartilage, the enteric and peripheral nervous systems and pigment cells.

Stroma

Interstitial tissue consisting of extracellular matrix and mesenchymal cells. The interface between stroma and adjacent epithelia and vessels is formed by a basement membrane layer.

Lateral line

A series of mechanosensory hair cell organs along the skin in fish and amphibia that detect changes in the surrounding water. Its precursor consists of neurogenic placodes, which migrate along defined paths and deposit clusters of cells behind them. These clusters differentiate into sensory hair cells that are analogous to those of the mammalian inner ear.

Matrigel plug assay

An experiment in which tumour cells are suspended in matrigel solution and injected into a mammal, usually a mouse or rat. Because of the avascular matrigel barrier, vessels from the host sprout into the transplant and generate a de novo vessel network.

Adherens junction

A punctated or linear cell–cell adhesion that contains cadherins and nectin, which are coupled to the actomyosin cytoskeleton by the adaptors α-, β- and γ-catenin and afadin (also known as AF6), respectively. Adherens junctions are dynamic structures that undergo continuous remodelling and provide cell–cell adhesion and signalling.

Integrin

A heterodimeric protein that consists of an α- and a β-chain that both mediate extracellular ligand binding and intracellular engagement of cytoskeletal and signalling proteins. Integrins provide adhesion and mechanotransduction as well as intracellular signal transduction.

Epithelial–mesenchymal transition

(EMT). The detachment of individual cells from an epithelium after downmodulation of cell–cell junctions, followed by single cell migration. The concept of EMT was established for morphogenic delamination of single cells into the mesenchyme and is discussed here in the context of early steps of cancer invasion.

Desmosomal protein

Desmoglein 1–4 and desmocollin 1–3 connect through desmosomal adaptor proteins (plakoglobin, plakophilin, desmoplakin and desmocollin) to the intermediate filament cytoskeleton. These cadherins form homophilic adhesions and provide mechanically strong intercellular junctions between epithelial cells.

Tight junction

A linear cell–cell adhesion complex in polarized epithelial and endothelial cells. Mediated by homophilic adhesion proteins, junction adhesion molecules, occludin and claudins, tight junctions form a tight barrier for the regulation of liquid, ion and nutrient flow across the epithelial barrier and contribute to cell polarity and signalling.

Pseudopodium

A morphologically dynamic cylindrical cell protrusion of <3 μm thickness. Pseudopodia are controlled by the small GTPase Rac and CDC42, result from rapid filamentous actin polymerization, and allow cells to elongate, probe and adhere to other cells and to the extracellular matrix.

Lamellipodium

A flat, cellular protrusion that is rich in branched actin filaments. Filament formation and branching are controlled by the small GTPase Rac and downstream effectors, including the actin-related protein (Arp)2/3 complex and formins, including mammalian diaphanous 1 (mDIA1; also known as DIAPH1) and mDIA2 (also known as DIAPH3).

Filopodium

A finger-like and highly dynamic cell protrusion, 1 μm in diameter and up to 5 μm in length. Filopodia are formed by anterograde polymerization of actin bundles in parallel and lack microtubules. Their formation is controlled by the small GTPase CDC42.

Mesenchymal–epithelial transition

An experimentally induced aggregation of moving individual cells to form a multicellular complex that maintains cell–cell junctions. Its role in physiological contexts is unclear.

Gap junction

An intercellular hexameric channel between directly adjacent cells that transfers ions, small compounds and messengers between the cytosol of both cells and provides adhesive coupling independent of channel function. Gap junctions synchronize mechanical and metabolic cell functions in multicellular tissues.

Collective amoeboid transition

The detachment of amoeboid cells from a multicellular complex as a consequence of loosened cell–cell junctions. Detached cells then use a leukocyte-like amoeboid migration mode because of the low adhesion and traction force generated.

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Friedl, P., Gilmour, D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10, 445–457 (2009). https://doi.org/10.1038/nrm2720

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