During collective migration, cells not only migrate in a coordinated manner but also migrate faster and in a more directed way than individual cells. The coordination and efficiency of collective migration relies on cellular interactions through soluble and contact-mediated signals.
Leader cells, which are generally localized at the front of the migrating group, have specific molecular features and morphological characteristics, which are reinforced by the soluble and contact-mediated signals present in their microenvironment.
Leader cells facilitate the directed migration of followers, directly by generating pulling forces and indirectly by modifying the composition and structure of the extracellular matrix.
Intercellular contacts between collectively migrating cells involving several sets of membrane proteins induce a local inhibition of locomotion through the regulation of RHO GTPases. Contact inhibition of locomotion is an essential event that promotes the coordinated polarization of collectively migrating cells.
Several lines of evidence have shown that the followers actively participate in the collective movement by communicating with one another and with the leaders, by generating forces and contributing to the generation of chemotactic gradients.
Collective cell migration has a key role during morphogenesis and during wound healing and tissue renewal in the adult, and it is involved in cancer spreading. In addition to displaying a coordinated migratory behaviour, collectively migrating cells move more efficiently than if they migrated separately, which indicates that a cellular interplay occurs during collective cell migration. In recent years, evidence has accumulated confirming the importance of such intercellular communication and exploring the molecular mechanisms involved. These mechanisms are based both on direct physical interactions, which coordinate the cellular responses, and on the collective cell behaviour that generates an optimal environment for efficient directed migration. The recent studies have described how leader cells at the front of cell groups drive migration and have highlighted the importance of follower cells and cell-cell communication, both between followers and between follower and leader cells, to improve the efficiency of collective movement.
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R.M.'s work was supported by grants from the UK Medical Research Council (MRC; J000655, M010465) and Biotechnology and Biological Sciences Research Council (BBSRC; M008517), and S.E.-M.'s work was supported by the French Institut National du Cancer, l'Association pour la Recherche contre le Cancer and La Ligue contre le Cancer.
The authors declare no competing financial interests.
Finger-like membrane projections that are frequently found at the leading edge of migrating cells. These membrane protrusions are formed by the polymerization of actin bundles and can be induced, in particular, by the small GTPase CDC42.
Thin sheet-like membrane extensions that are frequently found at the front of migrating cells. The formation of lamellipodia involves the polymerization of a branched actin meshwork and the formation of transient adhesions with the cell substrate.
A family of transmembrane proteins that are involved in the interaction of cells with protein fibres of the extracellular matrix (ECM). α- and β-integrins form heterodimers, whose conformation and affinity for the ECM is regulated by inside-out signalling. Upon engagement with the ECM, integrin dimers induce intracellular (outside-in) signalling.
The process by which cells undergo directed locomotion along a chemical gradient.
- Adherens junctions
Molecular complexes that enable intercellular interaction. Adherens junctions involve the homophilic interaction of classical cadherins and a large complex of cytosolic proteins (such as catenins), bridging cadherins to the cytoskeleton, including actin stress fibres.
- Nurse cells
Cells that contribute to the development of the oocyte in invertebrate organisms. In Drosophila melanogaster, 15 nurse cells are included in the egg chamber that provides the nutrients, RNA and proteins required for the growth of the oocyte.
- Focal adhesions
Molecular complexes that enable cell adhesion to the extracellular matrix. Focal adhesions involve the transmembrane protein family of integrins and a large complex of cytosolic proteins, bridging integrins to the cytoskeleton, including actin stress fibres.
Cell–cell adhesion complexes that are typically found in epithelial cells. Desmosomes involve specific members of the cadherin family of transmembrane adhesion proteins and are connected to keratin filaments.
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Mayor, R., Etienne-Manneville, S. The front and rear of collective cell migration. Nat Rev Mol Cell Biol 17, 97–109 (2016). https://doi.org/10.1038/nrm.2015.14
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