Mapping the dynamics of force transduction at cell–cell junctions of epithelial clusters

Ng, Mei Rosa; Besser, Achim; Brugge, Joan S.; Danuser, Gaudenz

doi:10.7554/elife.03282

Cited by 110 publications

(141 citation statements)

References 65 publications

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“…) forces between cells critically regulates collective migration and durotaxis. Much of the evidence for this concept has been indirectly inferred from whole-cell traction force and genetic and pharmacological manipulations of cadherins and myosin (30)(31)(32)(33). Our findings now provide direct evidence that single cytoskeletal structures in cells mediate tensile forces over long distances across a monolayer.…”

Section: Discussionmentioning

confidence: 58%

Geometry and network connectivity govern the mechanics of stress fibers

Kassianidou

Brand

Schwarz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Actomyosin stress fibers (SFs) play key roles in driving polarized motility and generating traction forces, yet little is known about how tension borne by an individual SF is governed by SF geometry and its connectivity to other cytoskeletal elements. We now address this question by combining single-cell micropatterning with subcellular laser ablation to probe the mechanics of single, geometrically defined SFs. The retraction length of geometrically isolated SFs after cutting depends strongly on SF length, demonstrating that longer SFs dissipate more energy upon incision. Furthermore, when cell geometry and adhesive spacing are fixed, cell-to-cell heterogeneities in SF dissipated elastic energy can be predicted from varying degrees of physical integration with the surrounding network. We apply genetic, pharmacological, and computational approaches to demonstrate a causal and quantitative relationship between SF connectivity and mechanics for patterned cells and show that similar relationships hold for nonpatterned cells allowed to form cell-cell contacts in monolayer culture. Remarkably, dissipation of a single SF within a monolayer induces cytoskeletal rearrangements in cells long distances away. Finally, stimulation of cell migration leads to characteristic changes in network connectivity that promote SF bundling at the cell rear. Our findings demonstrate that SFs influence and are influenced by the networks in which they reside. Such higher order network interactions contribute in unexpected ways to cell mechanics and motility.cytoskeleton | active cable model | actin | myosin | cell migration

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Section: Discussionmentioning

confidence: 58%

Geometry and network connectivity govern the mechanics of stress fibers

Kassianidou

Brand

Schwarz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The CC junctions dissociate in a force-dependent manner (13,20,26,27) according to a relationship that accounts for different bond rupture rates in two force regimes, similar to Evans and Ritchie's equations (22,28):…”

Section: Dynamics Of Cell-cell Junctionsmentioning

confidence: 99%

Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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Epithelial-to-mesenchymal transition (EMT) enables scattering of cell clusters and disseminates motile cells to distant locations in vivo during embryonic development and cancer metastasis. Both stiffness and topography of the extracellular matrix (ECM) have been shown to influence EMT. In this work, we examine how the integrity of epithelial cell clusters is regulated by subcellular forces, protrusions, and adhesions for varying ECM inputs, such as stiffness, topography, and dimensionality. Our model simulates multicell networks of defined sizes and shapes in ECMs of varied stiffness and geometry. The integrity of cell clusters is dictated by cell-cell junctions, which depend on subcellular forces and adhesion dynamics within each cell of the cluster. Our simulations demonstrate an enhanced dissociation of cell-cell junctions in stiffer and more confined three-dimensional (3D) environments, consistent with experimental findings. In narrow channels, the cell edges parallel to the axis of channels lose their cell-cell junctions more readily than those oriented in the perpendicular direction. The inhibition of protrusive activity and cell polarity disables confinement-dependent cell scattering. Here, cell adhesion and spreading along channel walls is found to be essential for scattering. The model also predicts that two-dimensional (2D) confinement of clusters restricts cell spreading and simultaneously blunts the confinement-sensitive cell scattering. This new, to our knowledge, multiscale model integrates molecular adhesion dynamics, subcellular forces, cellular deformation, and macroscale mechanical properties of the ECM to predict the state of cell clusters of defined shapes and sizes. The predictions made by our model not only match experimental findings from a number of experimental setups, but also provide a new conceptual framework for understanding mechanosensitive cell scattering and EMT.

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“…Thus, spatial polarization of integrins and cadherins creates a mechanical landscape that drives heterogeneity during stem cell differentiation. Using computational modeling and in vitro experimental approaches, Danuser and colleagues have recently quantified force transmission within multicellular clusters (Ng et al, 2014) and have demonstrated that the distribution of forces through Ecadherin cell-cell junctions is dynamic and fluctuates with local variations in cell-ECM adhesion and actomyosin contractility. Taken together, these studies demonstrate that a dialog between cadherins and integrins, which occurs through shifts in actomyosin contractility, determines the organization of molecular and mechanical signals at both the cell and tissue level.…”

Section: Regulation Of Mechanosignaling and Forces By Crosstalk Betwementioning

confidence: 99%

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

Mui

Chen

Assoian

2016

Journal of Cell Science

230

215

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Cadherins and integrins are intrinsically linked through the actin cytoskeleton and share common signaling molecules. Although mechanosensing by the integrin-actin axis has long been appreciated, a growing body of literature now demonstrates that cadherins also transduce and respond to mechanical forces. Mounting evidence shows that mechanically driven crosstalk between integrins and cadherins regulates the spatial distribution of these receptors, their signaling intermediates, the actin cytoskeleton and intracellular forces. This interplay between integrins and cadherins can control fibronectin matrix assembly and signaling, and a fine balance between traction forces at focal adhesions and intercellular tension at adherens junctions is crucial for directional collective cell migration. In this Commentary, we discuss two central ideas: (1) how the dynamic interplay between integrins and cadherins regulates the spatial organization of intracellular signals and the extracellular matrix, and (2) the emerging consensus that intracellular force is a central mechanism that dictates cell behavior, guides tissue development and ultimately drives physiology.

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Mapping the dynamics of force transduction at cell–cell junctions of epithelial clusters

Cited by 110 publications

References 65 publications

Geometry and network connectivity govern the mechanics of stress fibers

Geometry and network connectivity govern the mechanics of stress fibers

Scattering of Cell Clusters in Confinement

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

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