Cell Science at a Glance 3203 Mechanisms of Introduction Similarly to single-cell migration, collective Collective cell movement occurs when two or cell movement results from actomyosin collective cell migration more cells that retain their cell-cell junctions polymerization and contractility coupled to cell at a glance move together across a two-dimensional (2D) polarity; however, there are some key layer of extracellular matrix (ECM) or through a differences. Single-cell migration through Olga Ilina1,2 and Peter Friedl1,2,* three-dimensional (3D) interstitial tissue interstitial tissue is a cyclical five-step process, 1Department of Cell Biology, Nijmegen Centre for scaffold (Friedl and Gilmour, 2009; Friedl et al., comprising cell polarization and protrusion of Molecular Life Sciences, Radboud University 2004; Lecaudey and Gilmour, 2006; Rorth, the leading edge (driven by the actin Nijmegen, The Netherlands 2Rudolf Virchow Center for Experimental 2007). Time-lapse and morphological analyses cytoskeleton), followed by attachment of the Biomedicine and Department of Dermatology, suggest that collective cell movement is relevant leading edge to the substrate, proteolytic University of Würzburg, Germany for many processes in morphogenesis, tissue degradation of tissue components that *Author for correspondence ([email protected]) repair, and cancer invasion and metastasis physically confine the cell body, actomyosin Journal of Cell Science 122, 3203-3208 (Christiansen and Rajasekaran, 2006; Friedl contraction (leading to tension along the length Published by The Company of Biologists 2009 et al., 1995; Lecaudey and Gilmour, 2006; axis) and, finally, forward sliding of the cell rear doi:10.1242/jcs.036525 Vaughan and Trinkaus, 1966; Weijer, 2009). (Friedl and Wolf, 2009; Lauffenburger and This article is part of a Minifocus on collective cell Collective cell dynamics give rise to complex Horwitz, 1996). Whereas these principles are migration. For further reading, please see related changes in multicellular tissue structures, retained in collective cell movement, the main articles: ʻWound repair at a glanceʼ by Tanya Shaw and Paul Martin (J. Cell Sci. 122, 3209-3213) and including epithelial regeneration, the sprouting modification is that the cells remain coupled by ʻCollective cell migration in developmentʼ by Cornelis of vessels and ducts in angiogenesis and cell-cell junctions at the leading edge as well as Weijer (J. Cell Sci. 122, 3215-3223). branching morphogenesis, and the deregulated in lateral regions and inside the moving cell invasion of cell masses during cancer group (Friedl at el., 2004; Lecaudey and progression and consecutive tissue destruction. Gilmour, 2006; Rorth, 2007). Consequently, Journal of Cell Science (See poster insert) 3204 Journal of Cell Science 122 (18) collective cell migration differs from single-cell carcinoma cells (Nabeshima et al., 1998). It is 2004). However, their role in collective cell migration in the simultaneous coordinated probable that most cancer types comprise dynamics still needs to be elucidated. polarization of (often many) cells at the leading invasive zones of intact cell-cell cohesion edge of the cell collective; the translocation of and collective invasion (Christiansen and Desmosomes cells through physical coupling and drag force; Rajasekaran, 2006). Such collective invasion Desmosomal proteins are markers of epithelial the activity of actin-rich lamellae in multiple zones show expression of cell-cell adhesion differentiation, and loss of their expression cells along or underneath the cell collective; the molecules and gap junctions, which are results in the epithelial-mesenchymal transition secondary remodelling of the extracellular characteristic of collective cell migration (see during morphogenesis and cancer progression matrix along the migration track, leading to the below) (Gavert et al., 2008; Hsu et al., 2000; van (Lee et al., 2006; Chidgey and Dawson, 2007). formation of a basement membrane or Kempen et al., 2000), strongly suggesting that During epidermal regeneration, migrating the widening of a 3D track (macropatterning) to the mechanisms of collective migration apply to keratinocyte sheets retain desmosomal cell-cell encompass an increasing volume of the cell invasive cancers (Friedl, 2004; Hashizume et al., junctions while closing a wound (Shaw and mass; and the coordinated retraction of multiple 1996; Hegerfeldt et al., 2002; Langbein Martin, 2009). In addition, there is substantial cells at the rear end of the group (Friedl and et al., 2003; Nabeshima et al., 2000). The evidence that membrane-localized desmosomal Gilmour, 2009). molecular prerequisites for collective invasion proteins are expressed during collective For most types of collective cell migration, in different types of cancer, its interdependence migration in advanced epithelial cancer our understanding of specific molecular on other invasion modes (such as the epithelial- (Christiansen and Rajasekaran, 2006). mechanisms and their cooperation is incomplete; mesenchymal transition) and its contribution to Expression of desmocollins 1 and 3, which are however, if viewed in context, common themes cancer metastasis are currently unknown members of the desmosomal cadherin family, emerge. In this poster article, we provide an [discussed by Friedl and Gilmour (Friedl and increases in invasion regions of colorectal overview of the cellular and molecular Gilmour, 2009)]. adenocarcinomas, as detected by immuno - regulation of collective migration by combining histochemistry (Khan et al., 2006), and this is known aspects of collective migration in cancer Mechanisms of cell-cell cohesion and indicative of collective invasion. Squamous cell with aspects of collective migration in polarity within collectively migrating carcinomas of the skin retain functional morphogenesis and epidermal regeneration. The cell groups desmosomes at cell-cell junctions, which does aim is to generate one cohesive and thus Similarly to non-migrating epithelia, not seem to prevent aggressive tumour ‘idealized’ model (see poster). collectively migrating cell groups are connected behaviour or risk of metastasis (Kurzen et al., by cell-cell junctions that mediate cell-cell 2003). Settings for collective cell migration: cohesion, mechanical integrity, cell polarity and, morphogenesis, repair and cancer probably, direct cell-cell signalling. The types of Integrins Collective cell migration occurs in many cell-cell junctions utilized are those that are Integrins are heterodimeric cell-surface physiological and pathological processes, known to occur in epithelia and endothelia; here receptors that are typically involved in cell- including morphogenesis, tissue repair and they occur in the context of multicellular matrix interactions. The function of integrins cancer. In morphogenesis, all stages of the dynamics and tissue remodelling. in cell-cell interactions is poorly understood, Journal of Cell Science development of the multicellular organism show but recent data suggest that integrins are also collective migration, including branching Adherens junctions involved in formation of cell-cell contacts in morphogenesis of the tracheal system (Ghabrial Adhesive cell-cell coupling in all known forms collective cell migration. α5β1 integrin and Krasnow, 2006); the formation of mammary of collective cell migration is mediated by interacts with fibronectin along interfaces ducts in mouse and human explant models adherens-junction proteins, including cadherins between ovarian carcinoma cells (Casey et al., (Ewald et al., 2008); migrating border cells in and transmembrane proteins of the 2001) or fibroblasts (Salmenpera et al., 2008), the Drosophila ovary (Niewiadomska et al., immunoglobulin superfamily. During branching and blocking of β1-integrin function through 1999; Geisbrecht and Montell, 2002); and the morphogenesis in the mammary gland, lumenal the use of a function-perturbing antibody in migration of cells that form the lateral line epithelial cells within elongating ducts elongate migrating multicellular melanoma clusters primordium in zebrafish (Dambly-Chaudiere collectively while retaining E-cadherin along leads to loss of cell-cell cohesion followed et al., 2007; Lecaudey et al., 2008; Weijer, cell-cell interfaces (Ewald et al., 2008). In by cell detachment and the transition to 2009). During tissue repair, collective cell carcinoma cells, loss of expression amoeboid single-cell migration (Hegerfeldt migration of epidermal sheets occurs across the of E-cadherin, together with upregulation of et al., 2002). provisional wound-bed, leading to epidermal N-cadherin and neural cell adhesion molecules, wound closure (Farooqui and Fenteany, 2005; results in the onset of collective migration in Tight junctions Poujade et al., 2007). Likewise, collective which cell-cell junctions are retained; this Tight junctions and tight-junction-related strands of endothelial cells penetrate the process is often referred to as incomplete proteins (including claudins 1 and 4, occludin provisional wound bed and deliver neo-vessels epithelial-mesenchymal transition (Lee et al., and zona occludens 1; ZO-1) are present in into the regenerating neo-tissue (Schmidt et al., 2006; Lehembre et al., 2008). Immunoglobulin many invasion zones of squamous cell 2007). family members, including activated leukocyte carcinomas (Langbein et al., 2003) as well as in Similarly to morphogenetic movements, cell adhesion molecule (ALCAM, also known melanomas in vitro,