Control of cell–cell forces and collective cell dynamics by the intercellular adhesome

Abstract

Dynamics of epithelial tissues determines key processes in development, tissue healing, and cancer invasion. These processes are critically influenced by cell-cell adhesion forces. However, the identity of the proteins that resist and transmit forces at cell-cell junctions remains unclear, and how these proteins control tissue dynamics is largely unknown. Here we provide a systematic study of the interplay between cell-cell adhesion proteins, intercellular forces, and epithelial tissue dynamics. We show that collective cellular responses to selective perturbations of the intercellular adhesome conform to three mechanical phenotypes. These phenotypes are controlled by different molecular modules and characterized by distinct relationships between cellular kinematics and intercellular forces. We show that these forces and their rates can be predicted by the concentrations of cadherins and catenins. Unexpectedly, we identified different mechanical roles for P-cadherin and E-cadherin; while P-cadherin predicts levels of intercellular force, E-cadherin predicts the rate at which intercellular force builds up.

Emergent structures and dynamics of cell colonies by contact inhibition of locomotion

“…Then, assuming these parameter values are similar for MCF10a and MDCK cells, we estimate ψ := f cil /(2Dr ) ≈ 1 for both cell lines. Self-propulsion forces can be estimated from traction force measurements, which yield Fm ≈ 60 nN and Fm ≈ 25 nN in MCF10a and MDCK tissues, respectively (43). Finally, cell-cell and cell-substrate adhesion energies can be related to an effective elastic modulus Γ of an expanding monolayer and to the total cellular strain tot at which the expansion stops (44).…”

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…The mechanics of lateral sheet migration is not fully resolved. Likely, cryptic lamellipodia generate traction force toward the substrate along the sheet, whereas the apical cell-cell junctions transmit collective actomyosin contractility to enable slow movement along the basement membrane (Farooqui and Fenteany 2005;Zegers and Friedl 2014;Bazellieres et al 2015), but the role of additional rotational and turbulent movements remains to be clarified (Nanba et al 2015). By coupling apicobasal polarity with high junction stability, sheet migration along a two-dimensional (2D) substrate layer as guidance cue is a conserved and important type of collective migration of a mature epithelium.…”

“…1D) (Friedl et al 1995;Alexander et al 2008;Montell et al 2012). Epithelial sheet movement is initiated by a row of leader cells coupled to follower cells by AJs containing E-or P-cadherin (Chapnick and Liu 2014;Plutoni et al 2016), and sheet displacement depends on coordinated traction force generation between leader and follower cells, which are distributed across cell -cell junctions by the actomyosin cytoskeleton (Brugues et al 2014;Reffay et al 2014;Bazellieres et al 2015). Moving clusters can be epithelial, such as the border cells moving along the boundaries of large nurse cells of the developing Drosphila ovary, or mesenchymal, such as moving neoplastic sheets in rhabodomyosarcoma explant culture (Friedl et al 1995).…”

Active Vertex Model for Cell-Resolution Description of Epithelial Tissue Mechanics

“…These are reminiscent of the fluctuations observed in supercooled colloidal and molecular liquids approaching the glass transition [11] and include characteristic features of the dynamical and mechanical response, such as dynamical heterogeneities and heterogeneous stress patterns, that were first observed in glasses, colloids and granular materials and that have extensively been studied in soft condensed matter physics [15]. It has also been argued that the migration patterns are sensitive to the expression of different adhesion proteins [16] as well as to the properties of the extracellular environment [17], such as the stiffness of the substrate [18,19]. These observations lead to the development of the notion of plithotaxis [12], a universal mechanical principle akin to the more familiar chemotaxis, which states that each cell tends to move in a way that maintains minimal local intercellular shear stress.…”