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  • Review Article
  • Published:

Physical influences of the extracellular environment on cell migration

Nature Reviews Molecular Cell Biology volume 15, pages 813–824 (2014)Cite this article

Subjects

Key Points

  • Cells alter their migratory phenotypes and velocity in response to the physical properties of their extracellular environment.

  • Confinement, adhesion, stiffness and topology of the extracellular environment are key physical variables influencing cell migration.

  • Univariate profiles and phase diagrams enable an understanding of how physical variables influence cell migration.

  • Numerical simulations enable systematic exploration of the phase space to highlight regions for experimental exploration.

Abstract

The way in which a cell migrates is influenced by the physical properties of its surroundings, in particular the properties of the extracellular matrix. How the physical aspects of the cell's environment affect cell migration poses a considerable challenge when trying to understand migration in complex tissue environments and hinders the extrapolation of in vitro analyses to in vivo situations. A comprehensive understanding of these problems requires an integrated biochemical and biophysical approach. In this Review, we outline the findings that have emerged from approaches that span these disciplines, with a focus on actin-based cell migration in environments with different stiffness, dimensionality and geometry.

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Figure 1: Physical variables influencing cell migration.
Figure 2: Example of velocity and phenotypic phase space for cell migration with the location of univariate profiles and a bivariate phase diagram indicated.
Figure 3: Summary of studies examining the relationship between confinement, adhesion or rigidity, and migration velocity for extracellular matrix gels and microchannels.

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Acknowledgements

G.C. is supported by a University Research Fellowship from the Royal Society. E.S. is supported by Cancer Research UK.

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Authors and Affiliations

  1. London Centre for Nanotechnology, 17–19 Gordon Street, London, WC1H 0AH, UK

    Guillaume Charras

  2. Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK

    Guillaume Charras

  3. Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK

    Erik Sahai

Authors
  1. Guillaume Charras
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Correspondence to Guillaume Charras or Erik Sahai.

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PowerPoint slides

Glossary

Isotropic

Equal in all directions.

Integrin

A heterodimeric molecule that binds to a wide range of extracellular matrix molecules and some cell surface molecules. The specificity of integrins is determined by the combination of α- and β-subunits. Importantly, their conformation can be regulated to modify their affinity for ligands. They frequently cluster, leading to changes in avidity for the matrix. Their cytoplasmic tails recruit a range of signalling molecules.

Actin polymerization

The addition of actin monomers to actin filaments; actin polymerization adjacent to the plasma membrane generates force that moves the plasma membrane forward. Many regulatory molecules can promote either the formation of new actin filaments or the extension of existing ones. If these regulators are associated with the plasma membrane, then actin polymerization occurs in a polarized manner.

Actomyosin contraction

Myosin motors can interact with actin filaments. Hydrolysis of ATP by myosin moves the actin filament relative to myosin. Many myosins are dimeric and can therefore move two actin filaments relative to one another. Actin filaments and dimeric myosins can form higher-order contractile networks.

Lamellipodia

Planar cell protrusions that are driven by F-actin polymerization.

RAC1

A small G protein that indirectly regulates ARP2/3 function and promotes the formation of lamellipodia.

ARP2/3 actin nucleation complex

Actin-related protein 2 (ARP2) and ARP3 form part of a complex that nucleates the formation of new actin filaments. This complex preferentially initiates new filaments from the side of existing filaments, leading to a branched actin network. ARP2/3 function is particularly associated with the formation of planar actin-driven protrusions known as lamellipodia.

Filopodia

Fine protrusions of the plasma membrane that are driven by actin polymerization.

Membrane blebs

Spherical membrane bulges formed by the combination of internal hydrostatic pressure and weak points of either the actin cortex or its linkage to the plasma membrane. Blebs rapidly fill with cytoplasm but initially lack F-actin. Bleb growth is slowed by actin polymerization under the membrane.

Focal adhesions

Large patches of integrins that typically develop from focal complexes. They grow and are stabilized by the application of actomyosin-driven force.

Elastic modulus

A measure of the deformability of a material — measured in Pascals.

Mechanotransduction

The process by which physical properties of the cellular environment are converted into changes in cell signalling and cell state.

Stress fibres

Contractile actomyosin cables that usually span two points of attachment to the substrate.

Isometric tension

Tension within a structure that is not changing length.

Focal complexes

Clusters of integrin-mediated adhesions. These structures are linked to F-actin. They can form and turnover rapidly, or may mature into focal adhesions.

BAR proteins

(Bin1/Amphiphysin/Rvs167 proteins). A family of proteins characterized by a long and slightly curved shape that can interact with membranes.

Haptotaxis

Movement directed by an immobile gradient in matrix components.

Chemotaxis

Movement directed by a soluble chemical gradient.

Cadherins

Calcium-dependent cell–cell adhesion molecules. Cadherins form homodimers that link cells together. The intracellular domain of cadherins is coupled indirectly to F-actin via catenins and eplin.

Phase diagram

A diagram that can be used to graphically display complex relationships between two or three parameters and cell phenotype.

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Charras, G., Sahai, E. Physical influences of the extracellular environment on cell migration. Nat Rev Mol Cell Biol 15, 813–824 (2014). https://doi.org/10.1038/nrm3897

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