Collective Cell Migration in Tissue Building


Collective cell migration (CCM) is an essential process during tissue building and morphogenesis of animal body plans, but it can also occur in pathogenic situations. A detailed study of this cell behaviour in several model systems has allowed to determine that cells move coordinately but interact differently while migrating together, thus defining several categories of collective cell movements. They are regulated by guidance signals that act as chemoattractants and allow directionality of movement and whose levels, together with the action of repulsive molecular cues, influence this movement. Besides, cells in the moving group affect each other through cell–cell interactions but they also interplay with the environment. Here, we describe the specific features of CCM and its different manifestations in vivo. We also discuss the potential relevance of the results obtained in the study of this cell behaviour in deciphering the molecular and cellular mechanisms underlying tumour invasion and metastasis.

Key Concepts

  • Cells can move either individually or collectivelly.
  • Collective cell migration occurs during morphogenesis of animal body plans.
  • Abnormal collective migration underlies pathological states such as tumour cell invasion and metastasis.
  • During collective cell migration, groups of cells move together directionally and in a coordinated manner.
  • Collective cell movements are regulated by dynamic gradients of extracellular signalling molecules, environmental geometrical constraints and intercellular communication.
  • Different types of collective cell movements have been defined according to the interactions among the cells in the moving cluster.
  • The use of in vitro, in vivo and theoretical models is contributing to understand how collective cell migration occurs.

Keywords: collective migration; morphogenesis; cell signalling; cell behaviour; model systems; tumour invasion

Figure 1. Cell collectives follow different migrating strategies. Schematic representation of the different types of CCM. (a) Sheet migration, white arrows indicate the contribution of different cells to the net movement of the whole group. (b) Border cell migration, an example of a free group, the central red cells are immobile and are transported by the surrounding group through other cells of the Drosophila oocyte. (c) Chain (left) and stream (right) migration, red arrows indicate interactions between cells that contribute to their coordination via cell adhesion and CIL. The red line represents a pre‐existing structure (i.e. an axon) that guides cells. (d) Slug migration, the red line indicates a signalling trail that directs migration. (e) During branching, cells rearrange within the forming branches to build highly elaborated structures. (f) In sprouting morphogenesis, a tip cell (red) is specified and starts migrating, then adjacent cells (or stalk cells, in pink and light purple) follow it without loosing contact.
Figure 2. Drosophila dorsal closure as a model of sheet migration. (a) Schematic representation of a dorsal view of Drosophila embryos at different stages of the dorsal closure process. Magnification of the interface between epidermal and amnioserosa (AS) cells is shown at the left part of the panel. The actin cable (AC) is depicted in red and the leading edge (LE) cells are shadowed in grey. Coloured arrows at the right part of the panel indicate forces generated by AS cells (blue), the AC (red) and the zippering process (green). (b) Confocal image of an embryo at the dorsal closure stage stained with phalloidin to show actin structures. The region corresponds to the same magnified in (a). Red arrowheads point to filopodia extended by LE cells during dorsal closure. An AS cell has been outlined in red to indicate the area measured in (c). (c) Graphic representation of apical cell surface fluctuations of an AS cell from the beginning of dorsal closure to late stages of the process. (a) and (c) are reproduced with permission from Solon et al., © Elsevier.
Figure 3. Role of Notch signalling in tip/stalk cell specification during endothelial sprouting. (a) Cartoon showing the cooperation between VEGF and Notch signalling for sprout formation during the angiogenic process. Yellow cells present a balance between Notch and Dll4 expression, green cells respond to the high levels of VEGF upregulating Dll4 and acquiring tip cell behaviour. Dll4 activates Notch signalling in neighbouring cells (red) that are specified as stalk cells. (b–d) Confocal images of zebrafish 30 hpf stage embryos expressing EGFP in endothelial cells. (b) Segmental artery sprouts of wild‐type morphology. (c) Ectopic sprouts (arrows) are formed upon reduction of Notch signalling using a Rbpsuh morpholino oligonucleotide. (d) Upregulation of Notch signalling, through notch1a intracellular domain overexpression, abolishes sprout formation and only occasional sprouts (arrowhead) or cytoplasmic extensions (arrow) from dorsal aorta appear. (a) Adapted with permission from Eilken and Adams () © Elsevier. (b–d) Adapted with permission from Siekmann and Lawson () © Nature Publishing Group.
Figure 4. Ductal elongation during mammary gland development occurs without leading cellular extensions in a rearranging, multilayered cell epithelium. (a–a′′) Confocal images of an ex vivo elongating duct, in which labelling of F‐actin and nuclei are shown. As it can be seen in (a′), cells at the front of advancing mammary ducts form neither cellular extensions (such as filopodia) nor other actin‐rich protrusions. Moreover, as shown in (a′′), the tip of growing buds is composed of several cell layers. (b–b′′) Cell rearrangements during ductal elongation. The upper parts of the panels show frames from a time‐lapse movie in an extending duct labeled with CellTracker (red) and Sca‐1‐EGFP to track cells. The lower parts of the panels are schematic views of the corresponding movie frame in which individual cells are highlighted. Note that cells in the multilayered region of the extending duct continuously exchange positions during the process. Adapted with permission from Ewald et al., © Elsevier.


Almagro S, Durmort C, Chervin‐Pétinot A, et al. (2010) The motor protein myosin‐X transports VE‐cadherin along filopodia to allow the formation of early endothelial cell‐cell contacts. Molecular and Cellular Biology 30: 1703–1717.

Aman A and Piotrowski T (2010) Cell migration during morphogenesis. Developmental Biology 341: 20–33.

Belacortu Y and Paricio N (2011) Drosophila as a model of wound healing and tissue regeneration in vertebrates. Developmental Dynamics 240: 2379–2404.

Chapnick DA and Liu X (2014) Leader cells positioning drives woun‐directed collective migration in TGFb‐stimulated epithelial sheets. Molecular Biology of the Cell 25: 1586–1593.

Clay MR and Halloran MC (2010) Control of neural crest cell behavior and migration: insights from live imaging. Cell Adhesion & Migration 4: 586–594.

Drawbridge J and Steinberg MS (1996) Morphogenesis of the axolotl pronephric duct: a model system for the study of cell migration in vivo. International Journal of Developmental Biology 40: 709–713.

du Roure O, Saez A, Buguin A, et al. (2005) Force mapping in epithelial cell migration. Proceedings of the National Academy of Sciences of the United States of America 102: 2390–2395.

Ellertsdóttir E, Lenard A, Blum Y, et al. (2010) Vascular morphogenesis in the zebrafish embryo. Developmental Biology 341: 56–65.

Eilken HM and Adams RH (2010) Dynamics of endothelial cell behavior in sprouting angiogenesis. Current Opinion in Cell Biology 22: 617–625.

Etienne‐Manneville S (2014) Neighborly relations during collective migration. Current Opinion in Cell Biology 30: 51–59.

Ewald AJ, Brenot A, Duong M, Chan BS and Werb Z (2008) Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Developmental Cell 14: 570–581.

Ewald AJ, Huebner RJ, Palsdottir H, et al. (2012) Mammary collective cell migration involves transient loss of epithelial features and individual cell migration within the epithelium. Journal of Cell Science 125: 2638–2654.

Farooqui R and Fenteany G (2005) Multiple rows of cells behind an epithelial wound edge extend cryptic lamellipodia to collectively drive cell‐sheet movement. Journal of Cell Science 118: 51–63.

Fernández BG, Arias AM and Jacinto A (2007) Dpp signaling orchestrates dorsal closure by regulating cell shape changes both in the amnioserosa and in the epidermis. Mechanisms of Development 124: 884–897.

Friedl P and Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nature Reviews Molecular Cell Biology 10: 445–457.

Friedl P, Sahai E, Weiss S and Yamada KM (2012) New dimensions in cell migration. Nature Reviews Molecular Cell Biology 13: 743–747.

Gerhardt H, Golding M, Fruttiger M, et al. (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. Journal of Cell Biology 161: 1163–1177.

Gjorevski N and Nelson CM (2011) Integrated morphodynamic signaling of the mammary gland. Nature Reviews Molecular Cell Biology 12: 581–593.

Gorfinkiel N, Schamberg S and Blanchard GB (2011) Integrative approaches to morphogenesis: lessons from dorsal closure. Genesis 49: 522–533.

Gray RS, Cheung KJ and Ewald AJ (2010) Cellular mechanisms regulating epithelial morphogenesis and cancer invasion. Current Opinion in Cell Biology 22: 640–650.

Iber D and Menshykau D (2013) The control of branching morphogenesis. Open Biology 3: 130088.

Ilina O and Friedl P (2009) Mechanisms of collective cell migration at a glance. Journal of Cell Science 122: 3203–3208.

Iruela‐Arispe ML and Davis GE (2009) Cellular and molecular mechanisms of vascular lumen formation. Developmental Cell 16: 222–231.

Kaltschmidt JA, Lawrence N, Morel V, et al. (2002) Planar polarity and actin dynamics in the epidermis of Drosophila. Nature Cell Biology 4: 937–944.

Kiehart DP, Galbraith CG, Edwards KA, et al. (2000) Multiple forces contribute to cell sheet morphogenesis for dorsal closure in Drosophila. Journal of Cell Biology 149: 471–490.

Macias H and Hinck L (2012) Mammary gland development. Wiley Interdisciplinary Reviews: Developmental Biology 1: 533–557.

Martin P and Parkhurst SM (2004) Parallels between tissue repair and embryo morphogenesis. Development 131: 3021–3034.

Muñoz‐Soriano V, Belacortu Y and Paricio N (2012) Planar cell polarity signaling in collective cell movements during morphogenesis and disease. Current Genomics 13: 609–622.

Muñoz‐Soriano V, López‐Domenech S and Paricio N (2014) Why mammalian wound‐healing researchers may wish to turn to Drosophila as a model. Experimental Dermatology 23: 538–542.

Ochoa‐Espinosa A and Affolter M (2012) Branching morphogenesis: from cells to organs and back. Cold Spring Harbor Perspectives in Biology 4.

Omelchenko T, Vasiliev JM, Gelfand IM, Feder HH and Bonder EM (2003) Rho‐dependent formation of epithelial “leader” cells during wound healing. Proceedings of the National Academy of Sciences of the United States of America 100: 10788–10793.

Oubaha M, Lin MI, Margaron Y, et al. (2012) Formation of a PKCζ/β‐catenin complex in endothelial cells promotes angiopoietin‐1‐induced collective directional migration and angiogenic sprouting. Blood 120: 3371–3381.

Peralta XG, Toyama Y, Hutson MS, et al. (2007) Upregulation of forces and morphogenic asymmetries in dorsal closure during Drosophila development. Biophysical Journal 92: 2583–2596.

Phng LK and Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Developmental Cell 16: 196–208.

Pla P, Moore R, Morali OG, et al. (2001) Cadherins in neural crest cell development and transformation. Journal of Cellular Physiology 189: 121–132.

Poujade M, Grasland‐Mongrain E, Hertzog A, et al. (2007) Collective migration of an epithelial monolayer in response to a model wound. Proceedings of the National Academy of Sciences of the United States of America 104: 15988–15993.

Reffay M, Parrini MC, Cochet‐Escartin O, et al. (2014) Interplay of RhoA and mechanical forces in collective cell migration driven by leader cells. Nature Cell Biology 16: 217–223.

Ríos‐Barrera LD and Riesgo‐Escovar JR (2013) Regulating cell morphogenesis: the Drosophila Jun N‐terminal kinase pathway. Genesis 51: 147–162.

Rørth P (2009) Collective cell migration. Annual Review of Cell and Developmental Biology 25: 407–429.

Rørth P (2012) Fellow travelers: emergent properties of collective cell migration. EMBO Reports 13: 984–991.

Sawada M, Huang SH, Hirota Y, Kaneko N and Sawamoto K (2011) Neuronal migration in the adult brain. In: Seki T, Sawamoto K, Parent JM and Alvarez‐Buylla A, (eds). Neurogenesis in the Adult Brain II, pp. 319–336. Berlin, Heidelberg, Germany: Springer.

Siekmann AF, Covassin L and Lawson ND (2008) Modulation of VEGF signaling output by the Notch pathway. Bioessays 30: 303–313.

Siekmann AF and Lawson ND (2007) Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445: 781–784.

Solon J, Kaya‐Copur A, Colombelli J and Brunner D (2009) Pulsed forces timed by a ratchet‐like mechanism drive directed tissue movement during dorsal closure. Cell 137: 1331–1342.

Theveneau E and Mayor R (2013) Collective cell migration of epithelial and mesenchymal cells. Cellular and Molecular Life Sciences 70: 3481–3492.

Uriu K, Morelli LG and Oates AC (2014) Interplay between intercellular signaling and cell movement in development. Seminars in Cell & Developmental Biology 35: 66–72.

Varner VD and Nelson CM (2014) Cellular and physical mechanisms of branching morphogenesis. Development 141: 2750–2759.

Vedula SR, Ravasio A, Lim CT and Ladoux B (2013) Collective cell migration: a mechanistic perspective. Physiology (Bethesda) 28: 370–379.

Vitorino P and Meyer T (2008) Modular control of endothelial sheet migration. Genes & Development 22: 3268–3281.

Wang Q, Feng JJ and Pismen LM (2012) A cell‐level biomechanical model of Drosophila dorsal closure. Biophysical Journal 103: 2265–2274.

Weijer CJ (2009) Collective cell migration in development. Journal of Cell Science 122: 3215–3223.

Wells AR, Zou RS, Tulu US, et al. (2014) Complete canthi removal reveals that forces from the amnioserosa alone are sufficient to drive dorsal closure in Drosophila. Molecular Biology of the Cell 25: 3552–3568.

Further Reading

Ghysen A and Dambly‐Chaudière C (2007) The lateral line microcosmos. Genes & Development 21: 2118–2130.

Montell DJ, Yoon WH and Starz‐Gaiano M (2012) Group choreography: mechanisms orchestrating the collective movement of border cells. Nature Reviews Molecular Cell Biology 13: 631–645.

Theveneau E and Mayor R (2012) Neural crest migration: interplay between chemorepellents, chemoattractants, contact inhibition, epithelial‐mesenchymal transition, and collective cell migration. Wiley Interdisciplinary Reviews: Developmental Biology 1: 435–445.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Muñoz‐Soriano, Verónica, and Paricio, Nuria(May 2015) Collective Cell Migration in Tissue Building. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025975]