Inter-cellular forces orchestrate contact inhibition of locomotion.
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ABSTRACT:
SUBMITTER: Davis JR
PROVIDER: S-EPMC4398973 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cells organized in tissues exert forces on their neighbors and their environment. Those cellular forces determine tissue homeostasis as well as reorganization during embryonic development and wound healing. To understand how cellular forces are generated and how they can influence the tissue state, we develop a particle-based simulation model for adhesive cell clusters and monolayers. Cells are contractile, exert forces on their substrate and on each other, and interact through contact inhibition of locomotion (CIL), meaning that cell-cell contacts suppress force transduction to the substrate and propulsion forces align away from neighbors. Our model captures the traction force patterns of small clusters of nonmotile cells and larger sheets of motile Madin-Darby canine kidney (MDCK) cells. In agreement with observations in a spreading MDCK colony, the cell density in the center increases as cells divide and the tissue grows. A feedback between cell density, CIL, and cell-cell adhesion gives rise to a linear relationship between cell density and intercellular tensile stress and forces the tissue into a nonmotile state characterized by a broad distribution of traction forces. Our model also captures the experimentally observed tissue flow around circular obstacles, and CIL accounts for traction forces at the edge.
| S-EPMC4791011 | biostudies-other
Project description:Contact inhibition of locomotion is defined as the behavior of cells to cease migrating in their former direction after colliding with another cell. It has been implicated in multiple developmental processes and its absence has been linked to cancer invasion. Cellular forces are thought to govern this process; however, the exact role of traction through cell-matrix adhesions and tension through cell-cell adhesions during contact inhibition of locomotion remains unknown. Here we use neural crest cells to address this and show that cell-matrix adhesions are rapidly disassembled at the contact between two cells upon collision. This disassembly is dependent upon the formation of N-cadherin-based cell-cell adhesions and driven by Src and FAK activity. We demonstrate that the loss of cell-matrix adhesions near the contact leads to a buildup of tension across the cell-cell contact, a step that is essential to drive cell-cell separation after collision.
| S-EPMC5988567 | biostudies-literature
Project description:Contact guidance-the widely known phenomenon of cell alignment induced by anisotropic environmental features-is an essential step in the organization of adherent cells, but the mechanisms by which cells achieve this orientational ordering remain unclear. Here, we seeded myofibroblasts on substrates micropatterned with stripes of fibronectin and observed that contact guidance emerges at stripe widths much greater than the cell size. To understand the origins of this surprising observation, we combined morphometric analysis of cells and their subcellular components with a, to our knowledge, novel statistical framework for modeling nonthermal fluctuations of living cells. This modeling framework is shown to predict not only the trends but also the statistical variability of a wide range of biological observables, including cell (and nucleus) shapes, sizes, and orientations, as well as stress-fiber arrangements within the cells with remarkable fidelity with a single set of cell parameters. By comparing observations and theory, we identified two regimes of contact guidance: 1) guidance on stripe widths smaller than the cell size (w ≤ 160 μm), which is accompanied by biochemical changes within the cells, including increasing stress-fiber polarization and cell elongation; and 2) entropic guidance on larger stripe widths, which is governed by fluctuations in the cell morphology. Overall, our findings suggest an entropy-mediated mechanism for contact guidance associated with the tendency of cells to maximize their morphological entropy through shape fluctuations.
| S-EPMC6531843 | biostudies-literature
Project description:Contact inhibition of locomotion (CIL) is the process through which cells move away from each other after cell-cell contact, and it contributes to malignant invasion and developmental migration. Various cell types exhibit CIL, whereas others remain in contact after collision and may form stable junctions. To investigate what determines this differential behavior, we study neural crest cells, a migratory stem cell population whose invasiveness has been likened to cancer metastasis. By comparing pre-migratory and migratory neural crest cells, we show that the switch from E- to N-cadherin during EMT is essential for acquisition of CIL behavior. Loss of E-cadherin leads to repolarization of protrusions, via p120 and Rac1, resulting in a redistribution of forces from intercellular tension to cell-matrix adhesions, which break down the cadherin junction. These data provide insight into the balance of physical forces that contributes to CIL in cells in vivo.
| S-EPMC4552721 | biostudies-literature
Project description:The pioneering cell biologist Michael Abercrombie first described the process of contact inhibition of locomotion more than 50 years ago when migrating fibroblasts were observed to rapidly change direction and migrate away upon collision. Since then, we have gleaned little understanding of how contact inhibition is regulated and only lately observed its occurrence in vivo. We recently revealed that Drosophila macrophages (haemocytes) require contact inhibition for their uniform embryonic dispersal. Here, to investigate the role that contact inhibition plays in the patterning of haemocyte movements, we have mathematically analysed and simulated their contact repulsion dynamics. Our data reveal that the final pattern of haemocyte distribution, and the details and timing of its formation, can be explained by contact inhibition dynamics within the geometry of the Drosophila embryo. This has implications for morphogenesis in general as it suggests that patterns can emerge, irrespective of external cues, when cells interact through simple rules of contact repulsion.
| S-EPMC3509721 | biostudies-literature
Project description:Contact inhibition of locomotion (CIL) occurs when a cell stops migrating in a particular direction upon contact with another cell. Many cancer cells show Contact inhibition of locomotion when contacting one another but display contact-unimpeded migration following collision with noncancer cells. Here we review current understanding of Contact inhibition of locomotion, from Abercrombie's historical studies of cells in tissue culture to more recent analyses of Contact inhibition of locomotion in vivo. We discuss the cellular machinery required for CIL and the molecular signals that regulate it. We focus on our recent finding that in prostate cancer cells, Contact inhibition of locomotion is regulated by a balance between EphA and EphB receptor signalling. We show that, as recently described for chick heart fibroblasts, microtubule dynamics are required for Contact inhibition of locomotion in prostate cancer cells and we propose that stabilization of microtubules could account for defective Contact inhibition of locomotion between cancer cells and noncancer cells.
| S-EPMC3838626 | biostudies-literature
Project description:Contact inhibition of locomotion was discovered by Abercrombie more than 50 years ago and describes the behaviour of fibroblast cells confronting each other in vitro, where they retract their protrusions and change direction on contact. Its failure was suggested to contribute to malignant invasion. However, the molecular basis of contact inhibition of locomotion and whether it also occurs in vivo are still unknown. Here we show that neural crest cells, a highly migratory and multipotent embryonic cell population, whose behaviour has been likened to malignant invasion, demonstrate contact inhibition of locomotion both in vivo and in vitro, and that this accounts for their directional migration. When two migrating neural crest cells meet, they stop, collapse their protrusions and change direction. In contrast, when a neural crest cell meets another cell type, it fails to display contact inhibition of locomotion; instead, it invades the other tissue, in the same manner as metastatic cancer cells. We show that inhibition of non-canonical Wnt signalling abolishes both contact inhibition of locomotion and the directionality of neural crest migration. Wnt-signalling members localize at the site of cell contact, leading to activation of RhoA in this region. These results provide the first example of contact inhibition of locomotion in vivo, provide an explanation for coherent directional migration of groups of cells and establish a previously unknown role for non-canonical Wnt signalling.
| S-EPMC2635562 | biostudies-literature
Project description:Contact inhibition of locomotion (CIL), in which cells repolarize and move away from contact, is now established as a fundamental driving force in development, repair, and disease biology. Much of what we know of CIL stems from studies on two-dimensional (2D) substrates that do not provide an essential biophysical cue-the curvature of extracellular matrix fibers. We discover rules controlling outcomes of cell-cell collisions on suspended nanofibers and show them to be profoundly different from the stereotyped CIL behavior on 2D substrates. Two approaching cells attached to a single fiber do not repolarize upon contact but rather usually migrate past one another. Fiber geometry modulates this behavior; when cells attach to two fibers, reducing their freedom to reorient, only one cell repolarizes on contact, leading to the cell pair migrating as a single unit. CIL outcomes also change when one cell has recently divided and moves with high speed-cells more frequently walk past each other. Our computational model of CIL in fiber geometries reproduces the core qualitative results of the experiments robustly to model parameters. Our model shows that the increased speed of postdivision cells may be sufficient to explain their increased walk-past rate. We also identify cell-cell adhesion as a key mediator of collision outcomes. Our results suggest that characterizing cell-cell interactions on flat substrates, channels, or micropatterns is not sufficient to predict interactions in a matrix-the geometry of the fiber can generate entirely new behaviors.
| S-EPMC8000107 | biostudies-literature
Project description:Contact inhibition (CI) represents a crucial tumor-suppressive mechanism responsible for controlling the unbridled growth of cells, thus preventing the formation of cancerous tissues. CI can be further categorized into two distinct yet interrelated components: CI of locomotion (CIL) and CI of proliferation (CIP). These two components of CI have historically been viewed as separate processes, but emerging research suggests that they may be regulated by both distinct and shared pathways. Specifically, recent studies have indicated that both CIP and CIL utilize mechanotransduction pathways, a process that involves cells sensing and responding to mechanical forces. This review article describes the role of mechanotransduction in CI, shedding light on how mechanical forces regulate CIL and CIP. Emphasis is placed on filamin A (FLNA)-mediated mechanotransduction, elucidating how FLNA senses mechanical forces and translates them into crucial biochemical signals that regulate cell locomotion and proliferation. In addition to FLNA, trans-acting factors (TAFs), which are proteins or regulatory RNAs capable of directly or indirectly binding to specific DNA sequences in distant genes to regulate gene expression, emerge as sensitive players in both the mechanotransduction and signaling pathways of CI. This article presents methods for identifying these TAF proteins and profiling the associated changes in chromatin structure, offering valuable insights into CI and other biological functions mediated by mechanotransduction. Finally, it addresses unanswered research questions in these fields and delineates their possible future directions.
| S-EPMC10889191 | biostudies-literature
Project description:Directed cell migration in native environments is influenced by multiple migratory cues. These cues may include simultaneously occurring attractive soluble growth factor gradients and repulsive effects arising from cell-cell contact, termed contact inhibition of locomotion (CIL). How single cells reconcile potentially conflicting cues remains poorly understood. Here we show that a dynamic crosstalk between epidermal growth factor (EGF)-mediated chemotaxis and CIL guides metastatic breast cancer cell motility, whereby cells become progressively insensitive to CIL in a chemotactic input-dependent manner. This balance is determined via integration of protrusion-enhancing signalling from EGF gradients and protrusion-suppressing signalling induced by CIL, mediated in part through EphB. Our results further suggest that EphB and EGF signalling inputs control protrusion formation by converging onto regulation of phosphatidylinositol 3-kinase (PI3K). We propose that this intricate interplay may enhance the spread of loose cell ensembles in pathophysiological conditions such as cancer, and possibly other physiological settings.
| S-EPMC4391292 | biostudies-literature