Adhesion Hypothesis Research Articles

Pilin antigenic variants impact gonococcal lifestyle and antibiotic tolerance by modulating interbacterial forces.

Type 4 pili (T4P) are multifunctional filaments involved in adhesion, surface motility, biofilm formation, and horizontal gene transfer. These extracellular polymers are surface-exposed and, therefore, act as antigens. The human pathogen Neisseria gonorrhoeae uses pilin antigenic variation to escape immune surveillance, yet it is unclear how antigenic variation impacts most other functions of T4P. Here, we addressed this question by replacing the major pilin of a laboratory strain with pilins from clinical isolates. We reveal that the resulting strains vary substantially in their attractive forces. Strongly interacting bacteria form microcolonies while weakly interacting bacteria retain a planktonic lifestyle. In mixed microcolonies, different variant strains segregate in agreement with the differential strength of adhesion hypothesis. By combining structural predictions and laser tweezers experiments, we show that the C-terminal region of the pilin is crucial for attraction. Lifestyle affects growth kinetics and antibiotic tolerance. In the presence of ceftriaxone or ciprofloxacin, the killing kinetics indicate strongly increased tolerance of aggregating strains. We propose that pilin antigenic variation produces a mixed population containing variants optimized for growth, colonization, or survivability under external stress. Different environments select different variants, ensuring the survival and reproduction of the population as a whole.

Morphogenesis-inspired two-dimensional electrowetting in droplet networks

Living tissues dynamically reshape their internal cellular structures through carefully regulated cell-to-cell interactions during morphogenesis. These cellular rearrangement events, such as cell sorting and mutual tissue spreading, have been explained using the differential adhesion hypothesis, which describes the sorting of cells through their adhesive interactions with their neighbors. In this manuscript we explore a simplified form of differential adhesion within a bioinspired lipid-stabilized emulsion approximating cellular tissues. The artificial cellular tissues are created as a collection of aqueous droplets adhered together in a network of lipid membranes. Since this abstraction of the tissue does not retain the ability to locally vary the adhesion of the interfaces through biological mechanisms, instead we employ electrowetting with offsets generated by spatial variations in lipid compositions to capture a simple form of bioelectric control over the tissue characteristics. This is accomplished by first conducting experiments on electrowetting in droplet networks, next creating a model for describing electrowetting in collections of adhered droplets, then validating the model against the experimental measurements. This work demonstrates how the distribution of voltage within a droplet network may be tuned through lipid composition then used to shape directional contraction of the adhered structure using two-dimensional electrowetting events. Predictions from this model were used to explore the governing mechanics for complex electrowetting events in networks, including directional contraction and the formation of new interfaces.

Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVβ6/TGF-β Signaling Cascade.

Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell-cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression. We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell-cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVβ6 antibody. The DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVβ6 and subsequent transforming growth factor-β signaling as driver of cardiac fibrosis. Blocking integrin-αVβ6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo. We show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVβ6 and transforming growth factor-β signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.

Is cell segregation like oil and water: Asymptotic versus transitory regime.

Understanding the segregation of cells is crucial to answer questions about tissue formation in embryos or tumor progression. Steinberg proposed that separation of cells can be compared to the separation of two liquids. Such a separation is well described by the Cahn-Hilliard (CH) equations and the segregation indices exhibit an algebraic decay with exponent 1/3 with respect to time. Similar exponents are also observed in cell-based models. However, the scaling behavior in these numerical models is usually only examined in the asymptotic regime and these models have not been directly applied to actual cell segregation data. In contrast, experimental data also reveals other scaling exponents and even slow logarithmic scaling laws. These discrepancies are commonly attributed to the effects of collective motion or velocity-dependent interactions. By calibrating a 2D cellular automaton (CA) model which efficiently implements a dynamic variant of the differential adhesion hypothesis to 2D experimental data from Méhes et al., we reproduce the biological cell segregation experiments with just adhesive forces. The segregation in the cellular automaton model follows a logarithmic scaling initially, which is in contrast to the proposed algebraic scaling with exponent 1/3. However, within the less than two orders of magnitudes in time which are observable in the experiments, a logarithmic scaling may appear as a pseudo-algebraic scaling. In particular, we demonstrate that the cellular automaton model can exhibit a range of exponents ≤1/3 for such a pseudo-algebraic scaling. Moreover, the time span of the experiment falls into the transitory regime of the cellular automaton rather than the asymptotic one. We additionally develop a method for the calibration of the 2D Cahn-Hilliard model and find a match with experimental data within the transitory regime of the Cahn-Hilliard model with exponent 1/4. On the one hand this demonstrates that the transitory behavior is relevant for the experiment rather than the asymptotic one. On the other hand this corroborates the ambiguity of the scaling behavior, when segregation processes can be only observed on short time spans.

Adhesion-Based Self-Organization in Tissue Patterning.

Since the proposal of the differential adhesion hypothesis, scientists have been fascinated by how cell adhesion mediates cellular self-organization to form spatial patterns during development. The search for molecular tool kits with homophilic binding specificity resulted in a diverse repertoire of adhesion molecules. Recent understanding of the dominant role of cortical tension over adhesion binding redirects the focus of differential adhesion studies to the signaling function of adhesion proteins to regulate actomyosin contractility. The broader framework of differential interfacial tension encompasses both adhesion and nonadhesion molecules, sharing the common function of modulating interfacial tension during cell sorting to generate diverse tissue patterns. Robust adhesion-based patterning requires close coordination between morphogen signaling, cell fate decisions, and changes in adhesion. Current advances in bridging theoretical and experimental approaches present exciting opportunities to understand molecular, cellular, and tissue dynamics during adhesion-based tissue patterning across multiple time and length scales.

Differential Cellular Stiffness Contributes to Tissue Elongation on an Expanding Surface.

Pattern formation and morphogenesis of cell populations is essential for successful embryogenesis. Steinberg proposed the differential adhesion hypothesis, and differences in cell–cell adhesion and interfacial tension have proven to be critical for cell sorting. Standard theoretical models such as the vertex model consider not only cell–cell adhesion/tension but also area elasticity of apical cell surfaces and viscous friction forces. However, the potential contributions of the latter two parameters to pattern formation and morphogenesis remain to be determined. In this theoretical study, we analyzed the effect of both area elasticity and the coefficient of friction on pattern formation and morphogenesis. We assumed the presence of two cell populations, one population of which is surrounded by the other. Both populations were placed on the surface of a uniformly expanding environment analogous to growing embryos, in which friction forces are exerted between cell populations and their expanding environment. When the area elasticity or friction coefficient in the cell cluster was increased relative to that of the surrounding cell population, the cell cluster was elongated. In comparison with experimental observations, elongation of the notochord in mice is consistent with the hypothesis based on the difference in area elasticity but not the difference in friction coefficient. Because area elasticity is an index of cellular stiffness, we propose that differential cellular stiffness may contribute to tissue elongation within an expanding environment.

Model-Based Prediction of an Effective Adhesion Parameter Guiding Multi-Type Cell Segregation.

The process of cell-sorting is essential for development and maintenance of tissues. Mathematical modeling can provide the means to analyze the consequences of different hypotheses about the underlying mechanisms. With the Differential Adhesion Hypothesis, Steinberg proposed that cell-sorting is determined by quantitative differences in cell-type-specific intercellular adhesion strengths. An implementation of the Differential Adhesion Hypothesis is the Differential Migration Model by Voss-Böhme and Deutsch. There, an effective adhesion parameter was derived analytically for systems with two cell types, which predicts the asymptotic sorting pattern. However, the existence and form of such a parameter for more than two cell types is unclear. Here, we generalize analytically the concept of an effective adhesion parameter to three and more cell types and demonstrate its existence numerically for three cell types based on in silico time-series data that is produced by a cellular-automaton implementation of the Differential Migration Model. Additionally, we classify the segregation behavior using statistical learning methods and show that the estimated effective adhesion parameter for three cell types matches our analytical prediction. Finally, we demonstrate that the effective adhesion parameter can resolve a recent dispute about the impact of interfacial adhesion, cortical tension and heterotypic repulsion on cell segregation.

Disruption of the desmoglein adhesive interface causes Arrhythmogenic Cardiomyopathy

Arrhythmogenic Cardiomyopathy (ACM) in the majority of cases is caused by mutations in genes of the desmosomal cell-cell adhesion complex. ACM is characterized by progressive loss of cardiomyocytes with fibrosis, ventricular systolic dysfunction and life-threatening arrhythmias. Even though the pathological phenotype is well known, the underlying mechanisms are controversial and not well understood. Here, we tested the hypothesis that impaired adhesive function of desmosomes is central for disease development and progression. We generated a CRISPR/Cas9-based knock-in mouse model with exchange of tryptophan 2 to alanin in desmoglein-2 (Dsg2-W2A), which is a crucial desmosomal adhesion molecule in cardiomyocytes. This mutation, based on structural data, aims to abrogate the so-called tryptophan swap, a suggested central binding mechanism of Dsg2. In line with the dysfunctional adhesion hypothesis, mutant mice develop a severe cardiac phenotype recalling the characteristics of ACM including cardiac fibrosis, impaired systolic function and arrhythmia after adrenergic stimulation. While protein levels and localization of intercalated disc molecules were unchanged, structurally altered and even disrupted configurations of cardiomyocyte interfaces were evident on the ultrastructural level. Cell-cell dissociation assays and force spectroscopy measurements by atomic force microscopy confirmed the suspected adhesion defect of Dsg2-W2A molecules on cellular and molecular level. In summary, the adhesion-deficient Dsg2-W2A mouse model fulfils the criteria required to establish an ACM diagnosis. This shows that disruption of desmosomal adhesion is sufficient for ACM development with induction of the described phenotype. Further, the Dsg2-W2A mouse line represents a valuable model to study mechanisms of the disease and to identify novel treatments for ACM in vivo.

Dynamic conversion of cell sorting patterns in aggregates of embryonic stem cells with differential adhesive affinity

BackgroundMammalian early development comprises the proliferation, differentiation, and self-assembly of the embryonic cells. The classic experiment undertaken by Townes and Holtfreter demonstrated the ability of dissociated embryonic cells to sort and self-organize spontaneously into the original tissue patterns. Here, we further explored the principles and mechanisms underlying the phenomenon of spontaneous tissue organization by studying aggregation and sorting of mouse embryonic stem (ES) cells with differential adhesive affinity in culture.ResultsAs observed previously, in aggregates of wild-type and E-cadherin-deficient ES cells, the cell assemblies exhibited an initial sorting pattern showing wild-type cells engulfed by less adhesive E-cadherin-deficient ES cells, which fits the pattern predicted by the differential adhesive hypothesis proposed by Malcom Steinberg. However, in further study of more mature cell aggregates, the initial sorting pattern reversed, with the highly adhesive wild-type ES cells forming an outer shell enveloping the less adhesive E-cadherin-deficient cells, contradicting Steinberg’s sorting principle. The outer wild-type cells of the more mature aggregates did not differentiate into endoderm, which is known to be able to sort to the exterior from previous studies. In contrast to the naive aggregates, the mature aggregates presented polarized, highly adhesive cells at the outer layer. The surface polarity was observed as an actin cap contiguously spanning across the apical surface of multiple adjacent cells, though independent of the formation of tight junctions.ConclusionsOur experimental findings suggest that the force of differential adhesive affinity can be overcome by even subtle polarity generated from strong bilateral ligation of highly adhesive cells in determining cell sorting patterns.

The tight junction protein Claudin-5 limits endothelial cell motility.

Steinberg's differential adhesion hypothesis suggests that adhesive mechanisms are important for sorting of cells and tissues during morphogenesis (Steinberg, 2007). During zebrafish vasculogenesis, endothelial cells sort into arterial and venous vessel beds but it is unknown whether this involves adhesive mechanisms. Claudins are tight junction proteins regulating the permeability of epithelial and endothelial tissue barriers. Previously, the roles of claudins during organ development have exclusively been related to their canonical functions in determining paracellular permeability. Here, we use atomic force microscopy to quantify claudin-5-dependent adhesion and find that this strongly contributes to the adhesive forces between arterial endothelial cells. Based on genetic manipulations, we reveal a non-canonical role of Claudin-5a during zebrafish vasculogenesis, which involves the regulation of adhesive forces between adjacent dorsal aortic endothelial cells. In vitro and in vivo studies demonstrate that loss of claudin-5 results in increased motility of dorsal aorta endothelial cells and in a failure of the dorsal aorta to lumenize. Our findings uncover a novel role of claudin-5 in limiting arterial endothelial cell motility, which goes beyond its traditional sealing function during embryonic development.

Differential cell adhesion implemented by Drosophila Toll corrects local distortions of the anterior-posterior compartment boundary

Maintaining lineage restriction boundaries in proliferating tissues is vital to animal development. A long-standing thermodynamics theory, the differential adhesion hypothesis, attributes cell sorting phenomena to differentially expressed adhesion molecules. However, the contribution of the differential adhesion system during tissue morphogenesis has been unsubstantiated despite substantial theoretical support. Here, we report that Toll-1, a transmembrane receptor protein, acts as a differentially expressed adhesion molecule that straightens the fluctuating anteroposterior compartment boundary in the abdominal epidermal epithelium of the Drosophila pupa. Toll-1 is expressed across the entire posterior compartment under the control of the selector gene engrailed and displays a sharp expression boundary that coincides with the compartment boundary. Toll-1 corrects local distortions of the boundary in the absence of cable-like Myosin II enrichment along the boundary. The reinforced adhesion of homotypic cell contacts, together with pulsed cell contraction, achieves a biased vertex sliding action by resisting the separation of homotypic cell contacts in boundary cells. This work reveals a self-organizing system that integrates a differential adhesion system with pulsed contraction of cells to maintain lineage restriction boundaries.

Investigation on adhesive wear process of tool coating surface under high-adhesive rate environment in cutting Beryllium-copper C17200 alloy

Adhesive effect and sticking substances directly affects cutting process, tool life and geometry angle due to its randomness and unpredictability. This paper presents a single factor experiment based on adhesive rate variation trend and crystal adhesive hypothesis to understand the adhesive effect on tool damage. The results showed that the microstructures such as cracks, sticking substances and adhesive layer are the significant factor on tool damage process to make the coating more fragile and uncertain, and the adhesive effect appears a positive relationship with cutting performance, surface friction environment and wear life.

Dynamic cell-cell adhesion mediated by pericellular matrix interaction - a hypothesis.

Cell-cell adhesion strength, measured as tissue surface tension, spans an enormous 1000-fold range when different cell types are compared. However, the examination of basic mechanical principles of cell adhesion indicates that cadherin-based and related mechanisms are not able to promote the high-strength adhesion experimentally observed in many late embryonic or malignant tissues. Therefore, the hypothesis is explored that the interaction of the pericellular matrices of cells generates strong adhesion by a mechanism akin to the self-adhesion/self-healing of dynamically cross-linked hydrogels. Quantitative data from biofilm matrices support this model. The mechanism links tissue surface tension to pericellular matrix stiffness. Moreover, it explains the wide, matrix-filled spaces around cells in liquid-like, yet highly cohesive, tissues, and it rehabilitates aspects of the original interpretation of classical cell sorting experiments, as expressed in Steinberg's differential adhesion hypothesis: that quantitative differences in adhesion energies between cells are sufficient to drive sorting.

N-Cadherin Orchestrates Self-Organization of Neurons within a Columnar Unit in the Drosophila Medulla

Columnar structure is a basic unit of the brain, but the mechanism underlying its development remains largely unknown. The medulla, the largest ganglion of the Drosophila melanogaster visual center, provides a unique opportunity to reveal the mechanisms of 3D organization of the columns. In this study, using N-cadherin (Ncad) as a marker, we reveal the donut-like columnar structures along the 2D layer in the larval medulla that evolves to form three distinct layers in pupal development. Column formation is initiated by three core neurons, R8, R7, and Mi1, which establish distinct concentric domains within a column. We demonstrate that Ncad-dependent relative adhesiveness of the core columnar neurons regulates their relative location within a column along a 2D layer in the larval medulla according to the differential adhesion hypothesis. We also propose the presence of mutual interactions among the three layers during formation of the 3D structures of the medulla columns.SIGNIFICANCE STATEMENT The columnar structure is a basic unit of the brain, but its developmental mechanism remains unknown. The medulla, the largest ganglion of the fly visual center, provides a unique opportunity to reveal the mechanisms of 3D organization of the columns. We reveal that column formation is initiated by three core neurons that establish distinct concentric domains within a column. We demonstrate the in vivo evidence of N-cadherin-dependent differential adhesion among the core columnar neurons within a column along a 2D layer in the larval medulla. The 2D larval columns evolve to form three distinct layers in the pupal medulla. We propose the presence of mutual interactions among the three layers during formation of the 3D structures of the medulla columns.

Spatial Segregation and Boundary Formation in Breast Cancer Aggregates

In order to gain a greater understanding of spatial organization in cancerous tissues, we analyze the segregation patterns of 6 breast cell lines (MDA-MB-231, MDA-MB-468, MDA-MB-436, MDA-MB-157, ZR-75-1, and MCF-10A) of varying morphological classes and at varying stages along the epithelial-to-mesenchymal transition during the formation of mixed aggregates. Among these cell lines, sorting is generally robust. A sorting hierarchy is constructed by mixing cells and observing the development of the aggregate over time. To rationalize this sorting hierarchy, we consider sorting in the context of available adhesion proteins and cortex tension, cell properties that are typically considered in the differential adhesion hypothesis (DAH) and extensions of this hypothesis. We characterize the adhesion proteins mediating aggregate formation and find that these proteins play an important role in compaction speed, with high compaction speed dictating a preference for cell segregation to the inside of the aggregate. Among cell lines that share the same adhesion proteins, actomyosin contractility and cortex tension play distinct roles in further influencing sorting hierarchy. In cell lines utilizing classical cadherin-based compaction, increasing actomyosin contractility disrupts the aggregate, while in integrin-based compaction reducing contractility dramatically increases the compaction. To supplement the experiment, we perform Cellular Potts Model (CPM) simulations of sorting. The simulations replicate the sorting patterns observed experimentally both in cellular organization and morphology. Taken together, this suggests the application of the DAH as a minimum effective model for predicting sorting hierarchy among cell lines that may not necessarily conform to the usual tenets of the hypothesis.

Core/shell multicellular spheroids on chitosan as in vitro 3D coculture tumor models

An ideal in vitro drug screening model is important for the drug development. In addition to monoculture systems, 3 dimensional (3D) coculture systems are extensively used to simulate the in vivo tumor microenvironment as cell-cell and cell-extracellular matrix interactions within the tumor tissues can be mimicked. In this study, in vitro 3D suspension coculture multicellular spheroids with core/shell cell distribution were developed on chitosan-coated surfaces. Based on the characteristic of chitosan inhibiting cell adhesion, SW620 (colon cancer cell line), 3A6 (mesenchymal stem-like cell line) and Hs68 (foreskin fibroblast line) cells could aggregate to form 3D coculture spheroids with intimate cell contacts. When cells were cocultured on chitosan, 3A6 and Hs68 cells always located in the core of spheroids and were completely enveloped by SW620 cells due to their N-cadherin protein expression following the differential adhesion hypothesis. The core cells could be the feeder layers to stimulate the shell SW620 cells to enhance their mitochondria activity. Moreover, 3D coculture core/shell multicellular spheroids could enhance the resistance of SW620 cells against the cytotoxicity effect of chemotherapy drugs. To sum up, based on the specificity of the core/shell coculture multicellular spheroids, a novel in vitro tumor model was proposed in this study.

Modeling Colony Pattern Formation under Differential Adhesion and Cell Proliferation

Proliferation of individual cells is one of the hallmarks of living systems, and collectively the cells within a colony or tissue form highly structured patterns, influencing the properties at the population level. We develop a cellular automaton model that characterizes bacterial colony patterns emerging from the joint effect of cell proliferation and cell-cell differential adhesion. Through simulations and theoretical analysis akin to interface growth, we show that this model gives rise to novel properties consistent with recent experimental findings. We observe slower than exponential growth in the case of a single cell type as well as new colony patterns in the case of two cell types. In particular, engulfment of one cell type by the other is strongly enhanced compared to the prediction from the equilibrium differential adhesion hypothesis in the absence of proliferation. These observations provide new insights in predicting and characterizing colony morphology using experimentally accessible information such as single cell growth rate and cell adhesion strength.

Reduced immunohistochemical expression of CCN3 in vitiligo.

Defective adhesion seems to be involved in the chronic loss of melanocytes observed in vitiligo. Recent findings showed an association of genetic variants of an adhesion gene with vitiligo and reduced immunohistochemical expression of some adhesion molecules in vitiligo skin. To compare CCN3 immunohistochemical expression in lesional and non-lesional epidermis of individuals with vitiligo. A total of 66 skin specimens from 33 volunteers with vitiligo were analyzed by immunohistochemistry using anti-CCN3 antibodies. Absence of topical or systemic treatment for vitiligo over the previous 30 days and availability of an area of non-lesional skin for biopsy at least 15 cm away from any vitiliginous macules were the main inclusion criteria. A significant reduction of CCN3 expression was observed in lesional skin as compared to non-lesional skin (P = 0.001). Paraffin embedded skin samples do not allow investigation by molecular biology methods. Not all samples allowed analysis due to the lamina preparation technique. Complete clinical data was not available for all patients. Our results support the hypothesis of impaired cell adhesion in vitiligo suggested by genetic studies. The pattern of immunohistochemical expression suggests that vitiligo might be an epithelial disease and not just a melanocyte disorder.

Mean-cluster approach indicates cell sorting time scales are determined by collective dynamics.

Cell migration is essential to cell segregation, playing a central role in tissue formation, wound healing, and tumor evolution. Considering random mixtures of two cell types, it is still not clear which cell characteristics define clustering time scales. The mass of diffusing clusters merging with one another is expected to grow as t^{d/d+2} when the diffusion constant scales with the inverse of the cluster mass. Cell segregation experiments deviate from that behavior. Explanations for that could arise from specific microscopic mechanisms or from collective effects, typical of active matter. Here we consider a power law connecting diffusion constant and cluster mass to propose an analytic approach to model cell segregation where we explicitly take into account finite-size corrections. The results are compared with active matter model simulations and experiments available in the literature. To investigate the role played by different mechanisms we considered different hypotheses describing cell-cell interaction: differential adhesion hypothesis and different velocities hypothesis. We find that the simulations yield normal diffusion for long time intervals. Analytic and simulation results show that (i) cluster evolution clearly tends to a scaling regime, disrupted only at finite-size limits; (ii) cluster diffusion is greatly enhanced by cell collective behavior, such that for high enough tendency to follow the neighbors, cluster diffusion may become independent of cluster size; (iii) the scaling exponent for cluster growth depends only on the mass-diffusion relation, not on the detailed local segregation mechanism. These results apply for active matter systems in general and, in particular, the mechanisms found underlying the increase in cell sorting speed certainly have deep implications in biological evolution as a selection mechanism.

Microfilament-coordinated adhesion dynamics drives single cell migration and shapes whole tissues.

Cell adhesion to the substratum and/or other cells is a crucial step of cell migration. While essential in the case of solitary migrating cells (for example, immune cells), it becomes particularly important in collective cell migration, in which cells maintain contact with their neighbors while moving directionally. Adhesive coordination is paramount in physiological contexts (for example, during organogenesis) but also in pathology (for example, tumor metastasis). In this review, we address the need for a coordinated regulation of cell-cell and cell-matrix adhesions during collective cell migration. We emphasize the role of the actin cytoskeleton as an intracellular integrator of cadherin- and integrin-based adhesions and the emerging role of mechanics in the maintenance, reinforcement, and turnover of adhesive contacts. Recent advances in understanding the mechanical regulation of several components of cadherin and integrin adhesions allow us to revisit the adhesive clutch hypothesis that controls the degree of adhesive engagement during protrusion. Finally, we provide a brief overview of the major impact of these discoveries when using more physiological three-dimensional models of single and collective cell migration.