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      Collective and Individual Migration following the Epithelial-Mesenchymal Transition

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          Abstract

          During cancer progression, malignant cells in the tumour invade surrounding tissues. This transformation of adherent cells to a motile phenotype has been associated with the epithelial mesenchymal transition (EMT). Here, we show that EMT-activated cells migrate through micropillar arrays as a collectively advancing front that scatters individual cells. Individual cells with few neighbours dispersed with fast, straight trajectories, whereas cells that encountered many neighbours migrated collectively with epithelial biomarkers. We modelled these emergent dynamics using a physical analogy to solidification phase transitions in binary mixtures, and validated it using drug perturbations, which revealed that individually migrating cells exhibit diminished chemosensitivity. Our measurements also indicate a degree of phenotypic plasticity as cells interconvert between individual and collective migration. The study of multicellular behaviours with single-cell resolution should enable further quantitative insights into heterogeneous tumour invasion.

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          Most cited references33

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Collective migration of an epithelial monolayer in response to a model wound.

            Using an original microfabrication-based technique, we experimentally study situations in which a virgin surface is presented to a confluent epithelium with no damage made to the cells. Although inspired by wound-healing experiments, the situation is markedly different from classical scratch wounding because it focuses on the influence of the free surface and uncouples it from the other possible contributions such as cell damage and/or permeabilization. Dealing with Madin-Darby canine kidney cells on various surfaces, we found that a sudden release of the available surface is sufficient to trigger collective motility. This migration is independent of the proliferation of the cells that mainly takes place on the fraction of the surface initially covered. We find that this motility is characterized by a duality between collective and individual behaviors. On the one hand, the velocity fields within the monolayer are very long range and involve many cells in a coordinated way. On the other hand, we have identified very active "leader cells" that precede a small cohort and destabilize the border by a fingering instability. The sides of the fingers reveal a pluricellular actin "belt" that may be at the origin of a mechanical signaling between the leader and the followers. Experiments performed with autocrine cells constitutively expressing hepatocyte growth factor (HGF) or in the presence of exogenous HGF show a higher average velocity of the border and no leader.
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              THE CHEMOTACTIC EFFECT OF MIXTURES OF ANTIBODY AND ANTIGEN ON POLYMORPHONUCLEAR LEUCOCYTES

              An in vitro technique is described for assessing the chemotactic activity of soluble substances on motile cells. Antibody-antigen mixtures when incubated (37°C) in medium containing fresh (i.e. non-inactivated) normal rabbit serum exert a strong chemotactic effect on rabbit polymorphonuclear leucocytes. Results are described which indicate that, when antibody-antigen complexes are incubated (37°C) in fresh serum, a heat-stable (56°C) substance (or substances) is produced which acts directly as a chemotactic stimulus on the polymorphs. This heat-stable chemotactic substance is not produced when antibody-antigen complexes are incubated in serum which has been heated at 56°C for 30 minutes.
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                Author and article information

                Journal
                101155473
                30248
                Nat Mater
                Nat Mater
                Nature materials
                1476-1122
                30 July 2014
                17 August 2014
                November 2014
                01 May 2015
                : 13
                : 11
                : 1063-1071
                Affiliations
                [1 ] BioMEMS Resource Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown MA 02129
                [2 ] Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown MA 02129
                [3 ] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815
                Author notes
                [4]

                Current Address: Center for Biomedical Engineering, School of Engineering. Brown University, Providence RI 02912.

                Corresponding Author: Daniel Irimia ( dirimia@ 123456hms.harvard.edu ). BioMEMS Resource Center, Massachusetts General Hospital. 114 16 th St, Charlestown, MA 02129
                Article
                HHMIMS614941
                10.1038/nmat4062
                4209198
                25129619
                3264734d-8169-4b48-9b79-a460d3507f70
                History
                Categories
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                Materials science
                Materials science

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