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We analyze the mechanical properties of three epithelial/mesenchymal cell lines (MCF-10A, MDA-MB-231, MDA-MB-436) that exhibit a shift in E-, N-and P-cadherin levels characteristic of an epithelial−mesenchymal transition associated with processes such as metastasis, to quantify the role of cell cohesion in cell sorting and compartmentalization. We develop a unique set of methods to measure cell-cell adhesiveness, cell stiffness and cell shapes, and compare the results to predictions from cell sorting in mixtures of cell populations. We find that the final sorted state is extremely robust among all three cell lines independent of epithelial or mesenchymal state, suggesting that cell sorting may play an important role in organization and boundary formation in tumours. We find that surface densities of adhesive molecules do not correlate with measured cell-cell adhesion, but do correlate with cell shapes, cell stiffness and the rate at which cells sort, in accordance with an extended version of the differential adhesion hypothesis (DAH). Surprisingly, the DAH does not correctly predict the final sorted state. This suggests that these tissues are not behaving as immiscible fluids, and that dynamical effects such as directional motility, friction and jamming may play an important role in tissue compartmentalization across the epithelial−mesenchymal transition. transgress even the strong lineage boundaries, invading adjacent tissues. Therefore, a question of immediate practical importance is what changes allow metastatic cells to break through these boundaries, or conversely, what prevents non-metastatic tumour cells from leaving the compartment? Moreover, it is a fundamental question if a solid tumour behaves sufficiently like a fluid that surface tension-like effects hold cancer cells back at the tumour boundary.Metastasis has been attributed to tumour cells losing epithelial characteristics and acquiring a more migratory mesenchymal phenotype [9][10][11]. This change known as the epithelial−mesenchymal transition (EMT) is typically accompanied by a loss of specific types of cellular adhesion. While epithelial cells are closely connected via various types of cell junctions such as adherens junctions and desmosomes that allow them to form organized cell layers in vivo and cell clusters in vitro, mesenchymal cells are less constrained, contacting only through focal points [11]. During EMT, the expression of E-cadherin decreases while the expression of N-cadherin and other cadherins increases [12][13][14]. This might be the molecular origin for the change in adhesiveness, although recent work highlights that different cadherins play vastly different roles in regulating intercellular forces and adhesion [15]. In addition, EMT also causes a down-regulation of the keratin cytoskeleton and a replacement with vimentin [16], which also hinders desmosome formation. This leads to secondary effects that modulate cell-cell adhesion. However, it remains unclear how these processes interact with boundary formation and compartment m...

Collective cell migration is an important feature of wound healing, as well as embryonic and tumor development. The origin of collective cell migration is mainly intercellular interactions through effects such as a line tension preventing cells from detaching from the boundary. In contrast, in this study, we show for the first time that the formation of a constant cell front of a monolayer can also be maintained by the dynamics of the underlying migrating single cells. Ballistic motion enables the maintenance of the integrity of the sheet, while a slowed down dynamics and glass-like behavior cause jamming of cells at the front when two monolayers-even of the same cell type-meet. By employing a velocity autocorrelation function to investigate the cell dynamics in detail, we found a compressed exponential decay as described by the Kohlrausch-William-Watts function of the form C(δx) t ∼ exp (−(x/x 0 (t)) β(t) ), with 1.5 β(t) 1.8. This clearly shows that although migrating cells are an active, non-equilibrium system, the cell monolayer behaves in a glass-like way, which requires jamming as a part of intercellular interactions. Since it is the dynamics which determine the integrity of the cell sheet and its front for weakly interacting cells, it becomes evident why changes of the migratory behavior during epithelial to mesenchymal transition can result in the escape of single cells and metastasis.

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Plastic deformation in metallic glasses well below their glass transition temperatures T g occurs spatially heterogeneously within highly localized regions, termed shear transformation zones ͑STZs͒. Yet, their size and the number of atoms involved in a local shear event, remains greatly unclear. With the help of classical molecular dynamics ͑MD͒ computer simulations on plastic deformation of the model glass CuTi during pure shearing, we address this issue by evaluating correlations in atomic-scale plastic displacements, viz. the displacement correlation function. From the correlation length, a universal diameter of about 15 Å, or, equivalently, approximately 120 atoms is derived for a variety of conditions, such as variable strains, strain rates, temperatures, and boundary conditions. The physics of plastic deformation and flow in glassesone of the oldest engineering materials of mankind-is still poorly understood when compared to their crystalline counterparts, and thus has attracted increasing experimental and computational interests during the past decades. [1][2][3][4][5] In particular the highly heterogeneous, cooperative dynamics on multiple time and length scales, 6 and its influence on macroscopic dimensions is still greatly unclear, presumably due to the lack of an atomic-scale picture. This includes the impact on important material properties, such as elastic modulus, fracture behavior, and plastic flow. Adam and Gibbs 7 were the first to invoke the concept of a cooperative rearranging region ͑CRR͒ back in 1965 by proposing clusters that reorganize during shearing. As a main weakness of their treatment, however, they fail to predict a specific cluster size. Subsequent ideas developed by Cohen et al., 8 Spaepen,9 Argon, 10,11 and others describe flow and creep in metallic glasses as activated transformations in intrinsic dynamic heterogeneities, termed shear transformation zones ͑STZs͒. 12These models characterize plastic flow in metallic glasses during shearing as a local event appearing as a spontaneous and cooperative reorganization of individual clusters ͑STZs͒.13-16 As a major problem, however, the size of STZs still remains unclear, in particular for realistic material systems. A first hint to remedy this deficiency was provided by Debenedetti and Stillinger 17 who introduced a potential energy landscape model for the amorphous state and yielding in glasses. Johnson and Samwer 18 extended their treatment and proposed a size of STZs of the order of 100 atoms from energetic considerations.In the present investigations we employ molecular dynamics ͑MD͒ computer simulations to corroborate these predictions and link atomic-scale kinetics and mechanical properties across these length scales by determining the size of STZs as a function of macroscopic quantities. This is accomplished by investigating shear events below T g for the model glass CuTi. Evaluations of the plastic contribution to atomicscale displacements facilitate to identify cooperative motions, as expected in dynamical heterogeneities or ...

The mechanical properties of viral shells are crucial for viral assembly and infection. To study their distribution and heterogeneity on the viral surface, we performed atomistic force-probe molecular dynamics simulations of the complete shell of southern bean mosaic virus, a prototypical T = 3 virus, in explicit solvent. The simulation system comprised more than 4,500,000 atoms. To facilitate direct comparison with atomic-force microscopy (AFM) measurements, a Lennard-Jones sphere was used as a model of the AFM tip, and was pushed with different velocities toward the capsid protein at 19 different positions on the viral surface. A detailed picture of the spatial distribution of elastic constants and yielding forces was obtained that can explain corresponding heterogeneities observed in previous AFM experiments. Our simulations reveal three different deformation regimes: a prelinear regime of outer surface atom rearrangements, a linear regime of elastic capsid deformation, and a rearrangement regime that describes irreversible structural changes and the transition from elastic to plastic deformation. For both yielding forces and elastic constants, a logarithmic velocity dependency is evident over nearly two decades, the explanation for which requires including nonequilibrium effects within the established theory of enforced barrier crossing.

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Optical traps such as tweezers and stretchers are widely used to probe the mechanical properties of cells. Beyond their large range of applications, the use of infrared laser light in optical traps causes significant heating effects in the cell. This study investigated the effect of laser-induced heating on cell viability. Common viability assays are not very sensitive to damages caused in short periods of time or are not practicable for single cell analysis. We used cell spreading, a vital ability of cells, as a new sensitive viability marker. The optical stretcher, a two beam laser trap, was used to simulate heat shocks that cells typically experience during measurements in optical traps. The results show that about 60% of the cells survived heat shocks without vital damage at temperatures of up to 58 ± 2°C for 0.5 s. By varying the duration of the heat shocks, it was shown that 60% of the cells stayed viable when exposed to 48 ± 2°C for 5 s.