title: Cost-benefit analysis of the mechanisms that enable migrating cells to sustain motility upon changes in matrix environments.
abstract: Cells can move through extracellular environments with varying geometries and adhesive properties. Adaptation to these differences is achieved by switching between different modes of motility, including lamellipod-driven and blebbing motility. Further, cells can modulate their level of adhesion to the extracellular matrix (ECM) depending on both the level of force applied to the adhesions and cell intrinsic biochemical properties. We have constructed a computational model of cell motility to investigate how motile cells transition between extracellular environments with varying surface continuity, confinement and adhesion. Changes in migration strategy are an emergent property of cells as the ECM geometry and adhesion changes. The transition into confined environments with discontinuous ECM fibres is sufficient to induce shifts from lamellipod-based to blebbing motility, while changes in confinement alone within a continuous geometry are not. The geometry of the ECM facilitates plasticity, by inducing shifts where the cell has high marginal gain from a mode change, and conserving persistency where the cell can continue movement regardless of the motility mode. This regulation of cell motility is independent of global changes in cytoskeletal properties, but requires locally higher linkage between the actin network and the plasma membrane at the cell rear, and changes in internal cell pressure. In addition to matrix geometry, we consider how cells might transition between ECM of different adhesiveness. We find that this requires positive feedback between the forces cells apply on the adhesion points, and the strength of the cell-ECM adhesions on those sites. This positive feedback leads to the emergence of a small number of highly adhesive cores, similar to focal adhesions. While the range of ECM adhesion levels the cell can invade is expanded with this feedback mechanism; the velocities are lowered for conditions where the positive feedback is not vital. Thus, plasticity of cell motility sacrifices the benefits of specialization, for robustness.
authors: MRC/UCL Laboratory for Molecular Cell Biology, University College London, London, UK Biomolecular Modelling Laboratory, London Research Institute, Cancer Research UK, London, UK Tumour Cell Biology Laboratory, London Research Institute, Cancer Research UK, London, UK.
authors: Melda
authors: M
authors: Tozluoglu
authors: MRC/UCL Laboratory for Molecular Cell Biology, University College London, London, UK.
authors: Yanlan
authors: Y
authors: Mao
authors: Biomolecular Modelling Laboratory, London Research Institute, Cancer Research UK, London, UK paul.bates@crick.ac.uk.
authors: Paul A
authors: PA
authors: Bates
authors: Tumour Cell Biology Laboratory, London Research Institute, Cancer Research UK, London, UK erik.sahai@crick.ac.uk.
authors: Erik
authors: E
authors: Sahai
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology / Q000528:radiation effects; D000465:Algorithms; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D000066670:Cell Plasticity / Q000502:physiology; D003198:Computer Simulation; D017753:Ecosystem; D005109:Extracellular Matrix / Q000502:physiology*; D006801:Humans; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008954:Models, Biological
keywords: adaptation to extracellular matrix; cancer cell motility; cell–extracellular matrix adhesion feedback; plasma membrane blebbing; plasticity of motility