Fellow travellers: emergent properties of collective cell migration

Cells can migrate individually or collectively. Collective movement is common during normal development and is also a characteristic of some cancers. This review discusses recent insights into features that are unique to collective cell migration, as well as properties that emerge from these features. The first feature is that cells of the collective affect each other through adhesion, force‐dependent and signalling interactions. The second feature is that cells of the collective differ from one another: leaders from followers, tip from stalk and front from back. These are dynamic differences that are important for directional movement. Last, an unexpected property is discussed: epithelial cells can rotate persistently in constrained spaces.     

BIO-LGCA: A cellular automaton modelling class for analysing collective cell migration

Collective dynamics in multicellular systems such as biological organs and tissues plays a key role in biological development, regeneration, and pathological conditions. Collective tissue dynamics—understood as population behaviour arising from the interplay of the constituting discrete cells—can be studied with on- and off-lattice agent-based models. However, classical on-lattice agent-based models, also known as cellular automata, fail to replicate key aspects of collective migration, which is a central instance of collective behaviour in multicellular systems. To overcome drawbacks of classical on-lattice models, we introduce an on-lattice, agent-based modelling class for collective cell migration, which we call biological lattice-gas cellular automaton (BIO-LGCA). The BIO-LGCA is characterised by synchronous time updates, and the explicit consideration of individual cell velocities. While rules in classical cellular automata are typically chosen ad hoc, rules for cell-cell and cell-environment interactions in the BIO-LGCA can also be derived from experimental cell migration data or biophysical laws for individual cell migration. We introduce elementary BIO-LGCA models of fundamental cell interactions, which may be combined in a modular fashion to model complex multicellular phenomena. We exemplify the mathematical mean-field analysis of specific BIO-LGCA models, which allows to explain collective behaviour. The first example predicts the formation of clusters in adhesively interacting cells. The second example is based on a novel BIO-LGCA combining adhesive interactions and alignment. For this model, our analysis clarifies the nature of the recently discovered invasion plasticity of breast cancer cells in heterogeneous environments.     

Mechanical plasticity in collective cell migration

Collective cell migration is crucial to maintain epithelium integrity during developmental and repair processes. It requires a tight regulation of mechanical coordination between neighboring cells. This coordination embraces different features including mechanical self-propulsion of individual cells within cellular colonies and large-scale force transmission through cell–cell junctions. This review discusses how the plasticity of biomechanical interactions at cell–cell contacts could help cellular systems to perform coordinated motions and adapt to the properties of the external environment.     

Patchy stomatal conductance: emergent collective behaviour of stomata

Until recently, most scientists have tacitly assumed that individual stomata respond independently and similarly to stimuli, showing minor random variation in aperture and behaviour. This implies that stomatal behaviour should not depend on the scale of observation. However, it is now clear that these assumptions are often incorrect. Leaves frequently exhibit dramatic spatial and temporal heterogeneity in stomatal behaviour. This phenomenon, in which small 'patches' of stomata respond differently from those in adjacent regions of the leaf, is called 'patchy stomatal conductance'. It appears to represent a hitherto unknown type of emergent collective behaviour that manifests itself in populations of stomata in intact leaves.     

Multicellular scale front-to-rear polarity in collective migration

Collective cell migration does not only reflect the migration of cells at a similar speed and in the same direction, it also implies the emergence of new properties observed at the level of the cell group. This collective behavior relies on interactions between the cells and the establishment of a hierarchy amongst cells with leaders driving the group of followers. Here, we make the parallel between the front-to-rear polarity axis in single cell and the front-to-rear multicellular-scale polarity of a migrating collective which established through exchange of biochemical and mechanical information from the front to the rear and vice versa. Such multicellular-scale polarity gives the migrating group the possibility to better sense and adapt to energy, biochemical and mechanical constraints and facilitates migration over long distances in complex and changing environments.     

Local actin dynamics couple speed and persistence in a cellular Potts model of cell migration

Cell migration is astoundingly diverse. Molecular signatures, cell-cell interactions, and environmental structures each play their part in shaping cell motion, yielding numerous morphologies and migration modes. Nevertheless, in recent years, a simple unifying law was found to describe cell migration across many different cell types and contexts: faster cells turn less frequently. This universal coupling between speed and persistence (UCSP) was explained by retrograde actin flow from front to back, but it remains unclear how this mechanism generalizes to cells with complex shapes and cells migrating in structured environments, which may not have a well-defined front-to-back orientation. Here, we present an in-depth characterization of an existing cellular Potts model, in which cells polarize dynamically from a combination of local actin dynamics (stimulating protrusions) and global membrane tension along the perimeter (inhibiting protrusions). We first show that the UCSP emerges spontaneously in this model through a cross talk of intracellular mechanisms, cell shape, and environmental constraints, resembling the dynamic nature of cell migration in vivo. Importantly, we find that local protrusion dynamics suffice to reproduce the UCSP—even in cases in which no clear global, front-to-back polarity exists. We then harness the spatial nature of the cellular Potts model to show how cell shape dynamics limit both the speed and persistence a cell can reach and how a rigid environment such as the skin can restrict cell motility even further. Our results broaden the range of potential mechanisms underlying the speed-persistence coupling that has emerged as a fundamental property of migrating cells.     

Multi-cellular logistics of collective cell migration

During development, the formation of biological networks (such as organs and neuronal networks) is controlled by multicellular transportation phenomena based on cell migration. In multi-cellular systems, cellular locomotion is restricted by physical interactions with other cells in a crowded space, similar to passengers pushing others out of their way on a packed train. The motion of individual cells is intrinsically stochastic and may be viewed as a type of random walk. However, this walk takes place in a noisy environment because the cell interacts with its randomly moving neighbors. Despite this randomness and complexity, development is highly orchestrated and precisely regulated, following genetic (and even epigenetic) blueprints. Although individual cell migration has long been studied, the manner in which stochasticity affects multi-cellular transportation within the precisely controlled process of development remains largely unknown. To explore the general principles underlying multicellular migration, we focus on the migration of neural crest cells, which migrate collectively and form streams. We introduce a mechanical model of multi-cellular migration. Simulations based on the model show that the migration mode depends on the relative strengths of the noise from migratory and non-migratory cells. Strong noise from migratory cells and weak noise from surrounding cells causes "collective migration," whereas strong noise from non-migratory cells causes "dispersive migration." Moreover, our theoretical analyses reveal that migratory cells attract each other over long distances, even without direct mechanical contacts. This effective interaction depends on the stochasticity of the migratory and non-migratory cells. On the basis of these findings, we propose that stochastic behavior at the single-cell level works effectively and precisely to achieve collective migration in multi-cellular systems.     

Collective guidance of collective cell migration

Some cells migrate and find their way as solitary entities. However, during development of multicellular animals and possibly during tumor dissemination, cells often move as groups, associated tightly or loosely. Recent advances in live imaging have aided examination of such 'multicellular cell biology'. Here, I propose a model for how a group of cells can process and react to guidance information as a unit rather than as a gathering of solitary cells. Signaling pathways and regulatory mechanisms can differ substantially between solitary- and collective-guidance modes; a major difference being that, in collective guidance, similar to in bacterial chemotaxis, the signal need not be localized subcellularly within the responding cell. I suggest that collective-guidance signaling occurs alongside individual cell reactions. Both produce directional migration.     

Fluid flow and guidance of collective cell migration

Collective cell migration is emerging as a significant component of many biological processes including metazoan development, tissue maintenance and repair and tumor progression. Different contexts dictate different mechanisms by which migration is guided and maintained. In vascular endothelia subjected to significant shear stress, fluid flow is utilized to properly orient a migrating group of cells. Recently, we discovered that the developing zebrafish pronephric epithelium undergoes a similar response to luminal fluid flow, which guides pronephric epithelial migration towards the glomerulus. Intratubular migration leads to significant changes in kidney morphology. This novel process provides a powerful in vivo model for further exploration of the mechanisms underlying mechanotransduction and collective migration.Key words: collective migration, fluid flow, mechanotransduction, development, kidney, zebrafishThe term “collective cell migration” (collective motion) was first introduced to describe the behavior of starved Dictyostelium discoideum.¹ The term has rapidly gained general acceptance as encompassing a wide variety of coordinated cell migratory behaviors. A number of definitions have been proposed to unify the various collective migratory behaviors. Friedl et al.² defined it as “the movement of cell groups, sheets or strands consisting of multiple cells that are mobile yet simultaneously connected by cell-cell junctions.” This definition implies a number of features setting collective migration apart from other migratory behaviors. First, it points to the spatial restrictions on the individual cells within the migrating groups. The cells cannot leave the group and continue on their own. Therefore, they must respect the behavior of their neighbors and the overall migration occurs through the integration of individual cell activities across the collective. Second, it implies that different cells within the migrating group may play different roles. Some of them may not be migratory at all and simply “ride” the rest of the group, as indeed seen in border cell migration.³ Other cells within the group may further specialize into leaders and followers as can be seen in most current models of collective migration.⁴A variety of biological processes satisfy this definition. They include, among others, closure of wounded epithelial sheaths,³ physiological maintenance of intestinal epithelium,⁵ cancer invasion,^2,4,6 developmental processes of branching morphogenesis,^7,8 vascular sprouting,⁹ gastrulation,¹⁰ dorsal embryo closure,¹¹ as well as movements of some basal metazoan organisms such as sponges.¹² Over the years, a number of models emerged to study the process of collective migration.When starved, thousands of single cells of Dictyostelium discoideum aggregate and form a “slug” that migrates to the soil surface to form a fruiting body. This process has two general stages: the stage of aggregation, where individual migrating cells respond to cAMP concentration to form a multicellular aggregate¹³ and the stage of collective migration. In the latter stage, the leading (pre-stalk) cells of the slug secrete cAMP. In addition, they produce slime sheath that provides traction support for the aggregate. The slime sheath allows outermost cells of the aggregate to develop necessary traction for the entire slug to propel itself towards guidance cues. A number of molecular and cellular components have been recently identified to be important in this process, including integrin-, paxillin-like molecules and dynamic focal adhesion formation.¹⁴ Thus, Dictyostelium serves as a useful model for understanding the dynamic mechanisms of force formation in a migrating collective.Another well-established model of collective cell migration is the migration of border cells during ovary development in Drosophila. There, a small group of cells consisting of a central pair of polar cells surrounded by migratory outer border cells delaminate from the epithelium and migrate as a free group between nurse cells. Because of the tight nature of the migrating group, non-motile polar cells as well as mutant outer migratory cells can be carried within the group by their migratory companions.³ The migrating cluster uses nurse cells to generate the necessary traction to continue along the migratory path and rely on E-cadherin to accomplish this task.¹⁵ It has been proposed that the migrating border cell cluster is guided collectively wherein each outer border cell is inherently polarized, having an outer aspect and the inner aspect, so that the net migration of the cluster is simply the net of all the forces generated by the outer collective.¹⁶ It has been shown recently that both individual cell guidance and the collective cell guidance are at play in border cell migration.¹⁷Perhaps the best-studied examples of collective cell migration are found in the wound closure of epithelial sheets. Both kidney and gastric epithelial cell lines have been extensively studied in the wound closure assay to reveal important details of the collective migration that is a central process in wound repair. Recent studies have demonstrated the role of integrins, Rac, ERK, MAPK, Src and Pi3K among others as important molecular components of this processes.^18–21 A recent siRNA screen using breast epithelial cells identified a number of molecules that either inhibit or augment epithelial migration.²² This study revealed 42 genes previously unknown to be involved in migration. Many genes clustered within β-catenin, β1-integrin and actin networks in secondary analysis.While in vitro epithelial wound assays continue to provide insights into potential mechanisms of collective cell migration, the most developed in vivo vertebrate model comes from the studies of the zebrafish lateral line formation. In this process, the lateral line primordium cells move as a group in the anterior-posterior direction.^4,23 The migration is dependent on the interaction of stromal factor Cxcl12 along the guidance path and its receptor Cxcr4b.²⁴ The direction of migration is defined by the interplay between Fgf and Wnt signaling (rear and front of the migrating group, respectively). Wnt signaling in the front of the migrating lateral line inhibits Cxcr7b expression and promotes Cxcr4b expression. It also results in the secretion of Fgf ligands. Expression of sef at the front (also under control of Wnt) prevents Fgf from acting in this front domain. Fgf ligants interact with their receptors in the trailing end of the migrating group. As a result, the cells at the trailing end express dkk1 (to limit Wnt signaling) and Cxcr7b while downregulating Cxcr4b.^4,23,25,26 Thus, Cxcl12-Cxcr4b interaction is limited to the migration front. Cxcr7b expressed in the back of the migrating collective is believed to further interfere with Cxcl12-Cxcr4b interaction by sequestering Cxcl12. The net result of the differential signaling is the establishment of a distinct migratory front at the posterior aspect of the precursor population. At the same time, groups of cells at the back stop migrating and give rise to individual lateral line organs.The existence of a distinct migratory front is a unifying feature of all the models of collective migration described above. The migratory front defines the interface between the migratory collective and the tissues into which the migratory group advances. The front may be maintained by a stable pattern of signaling within the migrating group, as seen in lateral line migration where Wnt signaling at the front and FGF signaling at the back are maintained through mutual exclusion. Alternatively, the front may be maintained through spatial differences in concentrations of chemoattractants rendering the front of the group more migratory, as seen in the Drosophila border cell migration.³ In other systems, the migratory front may be maintained through cell-to-cell direct signaling, such as Notch signaling in determining the tips of vascular sprouts.⁹ Furthermore, migrating epithelial cultures in wound assays are inherently polarized by the presence of a free margin. Interestingly, the presence of the margin, which becomes the migratory front, is sufficient even in the absence of the wound to initiate a directed migration.²⁷ However, several new studies revealed that the existence of a distinct migratory front is not a universal or required feature of collective migration.^28–31Recently we discovered a novel form of collective migration that guides the morphogenesis and maturation of pronephric kidney.²⁸ The zebrafish pronephros is a simple bilaterally symmetrical structure consisting of two fused glomeruli, each connected to a pronephric tubule that runs posteriorly, eventually exiting at the level of the cloaca. The pronephros begins to function shortly after 1 dpf.²⁸ After the onset of its function, a signifi- cant maturation of the pronephros takes place, manifested at the structural level by the development of proximal convolution and re-positioning of nephron segment boundaries (Fig. 1). We demonstrated that both of these structural changes are a direct consequence of the collective epithelial migration that starts at about 30 hpf and lasts for the next three days. This proximal migration is governed by the onset of luminal fluid flow. The cells of the pronephric epithelium move enmasse towards the glomerulus and against the flow of urine. As a result, the proximal segment becomes compressed, shortened and convoluted. In contrast, the distal segment straightens and becomes longer (Fig. 1 and Suppl. Movie 1). This lengthening of the distal kidney is accompanied by cell proliferation that compensates for the proximal shift of kidney segments and allows for the en-masse migration to continue for three days.²⁸Open in a separate windowFigure 1Effect of pronephric migration on tubule architecture. (A) Schematic representation of zebrafish showing the pronephric kidney. Arrowhead points to the glomerulus. Arrow points to the pronephric tubule. (B) Pronephric architecture at 1 dpf before the onset of tubule flow. Dark shading indicates a distal segment. (C) Pronephric architecture at 3 dpf showing a markedly shortened and folded (convoluted) proximal segment. (D) Pronephric architecture at 3 dpf in the embryo with eliminated glomerular filtration. The position of the tubule convolution is now at the interface of the proximal and the distal tubules (see also Suppl. movie files 1 and 2).As mentioned above, this novel developmental process differs from most models of collective cell migration in at least one aspect; it lacks a distinct migratory front. In the absence of such front, the polarity of the migrating pronephric epithelium is established by using fluid flow as the guiding cue. When directed fluid flow is eliminated by obstructing the pronephros, the proximal migration is disrupted. Instead, the cells of the pronephric epithelium can often be seen migrating circumferentially, around the tube perimeter. This circumferential pseudo-migration correlates with the presence of local vortex currents in obstructed pronephroi due to the presence of beating cilia. Indeed, we failed to observe similar circumferential pseudomigratory behavior in paralyzed cilia mutants (unpublished data). In addition, we were able to engineer an ectopic convolution (about 500 µm distal to its normal location next to the glomerulus) by selectively eliminating proximal, but not distal sources of fluid flow (Fig. 1 and Suppl. Movie 2). This finding further supports the conclusion that luminal fluid flow guides the epithelial migration. It is still possible that different cells within the pronephric epithelium have distinct roles in orchestrating the migration. For instance, a small subset of cells could act as functional leaders and organize the migration process. Alternatively, luminal flow could directly interact with each migrating cell. Further studies should determine which scenario is present in the pronephros.There are at least two other systems where cell migration is governed by the mechanical forces generated by luminal fluid flow. Vascular endothelial cells respond to fluid shear stress, orient in the direction of the flow and migrate in the direction of shear force. This behavior is thought to be important in vascular remodeling.²⁹ A related model was developed in macaque placental trophoblast cells which demonstrate a similar behavior.³⁰ It is notable that in a wound assay, endothelial cells respond in a way similar to that in other in vitro wound models described above.³² Thus, more than one mode of guidance may be present in a given tissue.Significant advances have been made in our understanding of the cellular responses to shear stress in vascular endothelium. Endothelial cells sense and respond to fluid shear by utilizing a system of adhesion molecules including PECAM and VE-cadherin, integrin activation, activation of VEGFR, calcium influx, and modulation of the cytoskeleton by Rho family GTPases.^29,31 Recent evidence also suggests that sensory cilia play a role in the endothelial response to shear stress.^33,34 Fluid shear first induces lamellipodial cell extensions, followed by basal protrusions and new focal adhesion formation in the direction of the flow. Subsequent migration requires remodeling of adhesions and release of cell substratum attachments at the rear of the migrating cell.Migration of pronephric epithelial cells is likely to involve similar basic mechanisms. For instance, we have observed a strong correlation between the presence of directed lamellipodial extensions of epithelial cells on the tubule basement membranes and the basal phosphoFAK staining, suggesting that pronephric epithelial cells actively remodel their matrix attachments as they migrate. The similarities and differences between these two systems are likely to prove useful in determining how mechanical forces establish self-perpetuating cell movement. A notable difference between the pronephric cell migration and endothelial cell migration is that pronephric cells migrate against the flow as opposed to in the direction of the flow, suggesting that the exact nature of the process linking flow to migration may also be different.Several mechanisms may be at play in transducing the directional flow into directed migration of pronephric epithelia. First, ciliary function has been implicated in sensing fluid flow.³⁵ Thus, it is possible that bending the luminal cilia is key to the translation of luminal flow into collective epithelial cell migration. However, this potential mechanism was not supported by our observations. In particular, we tested the role of polycystins that are thought to be central to the flow sensing mechanism in the cilia.^33,36 We observed that polycystin morphants did not show an arrest or misorientation of migration until pronephric cycts were formed. This finding indicates that polycystins affect migration secondarily, due to pronephric obstruction and perturbation of flow, rather than by directly influencing epithelial migration. While polycystins do not appear to mediate mechanotransduction in pronephric epithelial migration, other members of the TRP ion channel family may be involved. Many TRP channels, such as TRPV, TRPC as well as other mechanosensitive ion channels, are thought to mediate transduction of mechanical stimuli into the intracellular signals.^37,38 It is possible that one or more such mechanisms are present in the pronephros.Alternatively, as discussed above, shear stress may be transduced at focal adhesions through integrin coupled intracellular signals with multiple potential intracellular targets, including Src, FAK, ILK, paxillin and p130Cas.³⁹ It has been shown, for example, that in cultured intestinal epithelial cells, a mechanical deformation of the substrate stimulates migration in FAK dependent manner.⁴⁰ Cell-cell junctions may also serve as a major site of mechanotransduction as was shown in vascular endothelia.³¹Other potential components of mechanotransduction include G-protein coupled receptors, which were shown to localize to the sites of focal adhesion and are known to be activated by shear stress and cyclic stretching.³⁸ Here, mechanical displacement may lead to the conformational change in the receptor molecule and the activation of downstream targets. In addition, Wnt and receptor tyrosine kinase signaling have been linked to mechanotransduction.^38,41 It remains to be determined which of these processes mediate the relation between pronephric flow and epithelial migration.It is possible, however, that multiple components (focal adhesion complexes, cell junctions, sensory cilia, etc.) interact with each other, and these interactions are integrated by the cell to generate a response to a mechanical stimulus. There is evidence showing that various components are indeed linked together by cytoskeleton.^34,42 The apical ciliary response to shear stress by cultured kidney cells (as measured by the cytoplasmic calcium increase) can be prevented by altering the integrity and the tensile properties of the cytoskeleton. The same result can be achieved by blocking the integrin interaction with extracellular matrix at the basal surface.⁴² Conversely, disrupting ciliary function in vascular endothelial cells significantly attenuates the overall response of the cell to fluid shear, the result that can also be achieved by disrupting cytoplasmic microtubule polymerization.³⁴These findings suggest a model in which multiple identified components of the mechanotransduction response are linked by cytoskeletal elements, that allow events at each specific location to influence the state of a different remote cell component directly.⁴³ For example, bending the cilium would have opposite mechanical effects on cell-cell junctions located in the direction of the bending, compared to those located on the opposite side.³⁴ Importantly, this mechanical communication is inherently bidirectional and would allow the cell to instantly integrate signals originating at different locations and initiate a robust and coordinated response to external mechanical cues.     

Fluid flow and guidance of collective cell migration

Collective cell migration is emerging as a significant component of many biological processes including metazoan development, tissue maintenance and repair and tumor progression. Different contexts dictate different mechanisms by which migration is guided and maintained. In vascular endothelia subjected to significant shear stress, fluid flow is utilized to properly orient a migrating group of cells. Recently, we discovered that the developing zebrafish pronephric epithelium undergoes a similar response to luminal fluid flow, which guides pronephric epithelial migration towards the glomerulus. Intratubular migration leads to significant changes in kidney morphology. This novel process provides a powerful in vivo model for further exploration of the mechanisms underlying mechanotransduction and collective migration.     

Roles of leader and follower cells in collective cell migration

Collective cell migration is a widely observed phenomenon during animal development, tissue repair, and cancer metastasis. Considering its broad involvement in biological processes, it is essential to understand the basics behind the collective movement. Based on the topology of migrating populations, tissue-scale kinetics, called the “leader–follower” model, has been proposed for persistent directional collective movement. Extensive in vivo and in vitro studies reveal the characteristics of leader cells, as well as the special mechanisms leader cells employ for maintaining their positions in collective migration. However, follower cells have attracted increasing attention recently due to their important contributions to collective movement. In this Perspective, the current understanding of the molecular mechanisms behind the “leader–follower” model is reviewed with a special focus on the force transmission and diverse roles of leaders and followers during collective cell movement.     

Enhanced persistence and collective migration in cooperatively aligning cell clusters

Most cells possess the capacity to locomote. Alone or collectively, this allows them to adapt, to rearrange, and to explore their surroundings. The biophysical characterization of such motile processes, in health and in disease, has so far focused mostly on two limiting cases: single-cell motility on the one hand and the dynamics of confluent tissues such as the epithelium on the other. The in-between regime of clusters, composed of relatively few cells moving as a coherent unit, has received less attention. Such small clusters are, however, deeply relevant in development but also in cancer metastasis. In this work, we use cellular Potts models and analytical active matter theory to understand how the motility of small cell clusters changes with N, the number of cells in the cluster. Modeling and theory reveal our two main findings: cluster persistence time increases with N, whereas the intrinsic diffusivity decreases with N. We discuss a number of settings in which the motile properties of more complex clusters can be analytically understood, revealing that the focusing effects of small-scale cooperation and cell-cell alignment can overcome the increased bulkiness and internal disorder of multicellular clusters to enhance overall migrational efficacy. We demonstrate this enhancement for small-cluster collective durotaxis, which is shown to proceed more effectively than for single cells. Our results may provide some novel, to our knowledge, insights into the connection between single-cell and large-scale collective motion and may point the way to the biophysical origins of the enhanced metastatic potential of small tumor cell clusters.     

Disentangling cadherin-mediated cell-cell interactions in collective cancer cell migration

Cell dispersion from a confined area is fundamental in a number of biological processes, including cancer metastasis. To date, a quantitative understanding of the interplay of single-cell motility, cell proliferation, and intercellular contacts remains elusive. In particular, the role of E- and N-cadherin junctions, central components of intercellular contacts, is still controversial. Combining theoretical modeling with in vitro observations, we investigate the collective spreading behavior of colonies of human cancer cells (T24). The spreading of these colonies is driven by stochastic single-cell migration with frequent transient cell-cell contacts. We find that inhibition of E- and N-cadherin junctions decreases colony spreading and average spreading velocities, without affecting the strength of correlations in spreading velocities of neighboring cells. Based on a biophysical simulation model for cell migration, we show that the behavioral changes upon disruption of these junctions can be explained by reduced repulsive excluded volume interactions between cells. This suggests that in cancer cell migration, cadherin-based intercellular contacts sharpen cell boundaries leading to repulsive rather than cohesive interactions between cells, thereby promoting efficient cell spreading during collective migration.