Mechanisms of collective cell migration at a glance

Abstract

This article is part of a Minifocus on collective cell migration. For further reading, please see related articles: `Wound repair at a glance' by Tanya Shaw and Paul Martin (J. Cell Sci.122, 3209-3213) and `Collective cell migration in development' by Cornelis Weijer (J. Cell Sci.122, 3215-3223).Collective cell movement occurs when two or more cells that retain their cell-cell junctions move together across a two-dimensional (2D) layer of extracellular matrix (ECM) or through a three-dimensional (3D) interstitial tissue scaffold (Friedl and Gilmour, 2009; Friedl et al., 2004; Lecaudey and Gilmour, 2006; Rorth, 2007). Time-lapse and morphological analyses suggest that collective cell movement is relevant for many processes in morphogenesis, tissue repair, and cancer invasion and metastasis (Christiansen and Rajasekaran, 2006; Friedl et al., 1995; Lecaudey and Gilmour, 2006; Vaughan and Trinkaus, 1966; Weijer, 2009). Collective cell dynamics give rise to complex changes in multicellular tissue structures, including epithelial regeneration, the sprouting of vessels and ducts in angiogenesis and branching morphogenesis, and the deregulated invasion of cell masses during cancer progression and consecutive tissue destruction.Similarly to single-cell migration, collective cell movement results from actomyosin polymerization and contractility coupled to cell polarity; however, there are some key differences. Single-cell migration through interstitial tissue is a cyclical five-step process, comprising cell polarization and protrusion of the leading edge (driven by the actin cytoskeleton), followed by attachment of the leading edge to the substrate, proteolytic degradation of tissue components that physically confine the cell body, actomyosin contraction (leading to tension along the length axis) and, finally, forward sliding of the cell rear (Friedl and Wolf, 2009; Lauffenburger and Horwitz, 1996). Whereas these principles are retained in collective cell movement, the main modification is that the cells remain coupled by cell-cell junctions at the leading edge as well as in lateral regions and inside the moving cell group (Friedl at el., 2004; Lecaudey and Gilmour, 2006; Rorth, 2007). Consequently, collective cell migration differs from single-cell migration in the simultaneous coordinated polarization of (often many) cells at the leading edge of the cell collective; the translocation of cells through physical coupling and drag force; the activity of actin-rich lamellae in multiple cells along or underneath the cell collective; the secondary remodelling of the extracellular matrix along the migration track, leading to the formation of a basement membrane or the widening of a 3D track (macropatterning) to encompass an increasing volume of the cell mass; and the coordinated retraction of multiple cells at the rear end of the group (Friedl and Gilmour, 2009).For most types of collective cell migration, our understanding of specific molecular mechanisms and their cooperation is incomplete; however, if viewed in context, common themes emerge. In this poster article, we provide an overview of the cellular and molecular regulation of collective migration by combining known aspects of collective migration in cancer with aspects of collective migration in morphogenesis and epidermal regeneration. The aim is to generate one cohesive and thus `idealized' model (see poster).Collective cell migration occurs in many physiological and pathological processes, including morphogenesis, tissue repair and cancer. In morphogenesis, all stages of the development of the multicellular organism show collective migration, including branching morphogenesis of the tracheal system (Ghabrial and Krasnow, 2006); the formation of mammary ducts in mouse and human explant models (Ewald et al., 2008); migrating border cells in the Drosophila ovary (Niewiadomska et al., 1999; Geisbrecht and Montell, 2002); and the migration of cells that form the lateral line primordium in zebrafish (Dambly-Chaudiere et al., 2007; Lecaudey et al., 2008; Weijer, 2009). During tissue repair, collective cell migration of epidermal sheets occurs across the provisional wound-bed, leading to epidermal wound closure (Farooqui and Fenteany, 2005; Poujade et al., 2007). Likewise, collective strands of endothelial cells penetrate the provisional wound bed and deliver neo-vessels into the regenerating neo-tissue (Schmidt et al., 2007).Similarly to morphogenetic movements, collective movement occurs in many cancers in which cells are not completely de-differentiated, including rhabdomyosarcoma, oral squamous cell carcinoma and breast cancer (Christiansen and Rajasekaran, 2006; Friedl et al., 1995; Gagglioli et al., 2007), and in colorectal carcinoma cells (Nabeshima et al., 1998). It is probable that most cancer types comprise invasive zones of intact cell-cell cohesion and collective invasion (Christiansen and Rajasekaran, 2006). Such collective invasion zones show expression of