No abstract

Each cell comprising an intact, healthy, confluent epithelial layer ordinarily remains sedentary, firmly adherent to and caged by its neighbors, and thus defines an elemental constituent of a solidlike cellular collective [1,2]. After malignant transformation, however, the cellular collective can become fluid-like and migratory, as evidenced by collective motions that arise in characteristic swirls, strands, ducts, sheets, or clusters [3,4]. To transition from a solid-like to a fluid-like phase and thereafter to migrate collectively, it has been recently argued that cells comprising the disordered but confluent epithelial collective can undergo changes of cell shape so as to overcome geometric constraints attributable to the newly discovered phenomenon of cell jamming and the associated unjamming transition (UJT) [1,2,[5][6][7][8][9]. Relevance of the jamming concept to carcinoma cells lines of graded degrees of invasive potential has never been investigated, however. Using classical in vitro cultures of six breast cancer model systems, here we investigate structural and dynamical signatures of cell jamming, and the relationship between them [1,2,10,11]. In order of roughly increasing invasive potential as previously reported, model systems examined included MCF10A, MCF10A.Vector; MCF10A. MCF10.ErbB2, MCF10AT;. Migratory speed depended on the particular cell line. Unsurprisingly, for example, the

Pattern-dependent collective behaviors of cells have recently raised intensive attention. However, the underlying mechanisms that regulate these behaviors are largely elusive. Here, we report a quantitative study, combining experiment and modeling, on cell polarization and arrangement on a micropatterned substrate. We show that cells exhibit position-dependent collective behaviors that can be regulated by geometry and stiffness of the patterned substrate. We find that the driving force for these collective behaviors is the in-plane maximum shear stress in the cell layer that directs the arrangement of cells. The larger the shear stress, the more the cells preferentially align and polarize along the direction of the maximum principal stress. We also find that the aspect ratio of cell polarization shape and the degree to which cells preferentially align along the direction of maximum principal stress exhibit a biphasic dependence on substrate rigidity, corresponding to our quantitative predictions that the magnitude of the maximum shear stress is biphasically dependent on the stiffness of the substrate. As such, the driving force of these cell collective behaviors can be quantified using the maximum shear stress.

α-Actinin-4 (ACTN4) bundles and cross-links actin filaments to confer mechanical resilience to the reconstituted actin network. How this resilience is built and dynamically regulated in the podocyte, and the cause of its failure in ACTN4 mutation-associated focal segmental glomerulosclerosis (FSGS), remains poorly defined. Using primary podocytes isolated from wild-type (WT) and FSGS-causing point mutant Actn4 knockin mice, we report responses to periodic stretch. While WT cells largely maintained their F-actin cytoskeleton and contraction, mutant cells developed extensive and irrecoverable reductions in these same properties. This difference was attributable to both actin material changes and a more spatially correlated intracellular stress in mutant cells. When stretched cells were further challenged using a cell adhesion assay, mutant cells were more likely to detach. Together, these data suggest a mechanism for mutant podocyte dysfunction and loss in FSGS-it is a direct consequence of mechanical responses of a cytoskeleton that is brittle.