Infiltration of tumor spheroids by activated immune cells.

Recent years have seen a tremendous growth of interest in understanding the role that the adaptive immune system could play in interdicting tumor progression. In this context, it has been shown that the density of adaptive immune cells inside a solid tumor serves as a favorable prognostic marker across different types of cancer. The exact mechanisms underlying the degree of immune cell infiltration is largely unknown. Here, we quantify the temporal dynamics of the density profile of activated immune cells around a solid tumor spheroid. We propose a computational model incorporating immune cells with active, persistent movement and a proliferation rate that depends on the presence of cancer cells, and show that the model able to reproduce semi-quantitatively the experimentally measured infiltration profile. Studying the density distribution of immune cells inside a solid tumor can help us better understand immune trafficking in the tumor micro-environment, hopefully leading towards novel immunotherapeutic strategies.

Resonant Diffusion of a Gravitactic Circle Swimmer.

We investigate the dynamics of a single chiral active particle subject to an external torque due to the presence of a gravitational field. Our computer simulations reveal an arbitrarily strong increase of the long-time diffusivity of the gravitactic agent when the external torque approaches the intrinsic angular drift. We provide analytic expressions for the mean-square displacement in terms of eigenfunctions and eigenvalues of the noisy-driven-pendulum problem. The pronounced maximum in the diffusivity is then rationalized by the vanishing of the lowest eigenvalues of the Fokker-Planck equation for the angular motion as the rotational diffusion decreases and the underlying classical bifurcation is approached. A simple harmonic-oscillator picture for the barrier-dominated motion provides a quantitative description for the onset of the resonance while its range of validity is determined by the crossover to a critical-fluctuation-dominated regime.

Revisiting the emergence of order in active matter.

The emergence of orientational order plays a central role in active matter theory and is deeply based in the study of active systems with a velocity alignment mechanism, whose most prominent example is the so-called Vicsek model. Such active systems have been used to describe bird flocks, bacterial swarms, and active colloidal systems, among many other examples. Under the assumption that the large-scale properties of these models remain unchanged as long as the polar symmetry of the interactions is not affected, implementations have been performed using, out of convenience, either additive or non-additive interactions; the latter are found for instance in the original formulation of the Vicsek model. Here, we perform a careful analysis of active systems with velocity alignment, comparing additive and non-additive interactions, and show that the macroscopic properties of these active systems are fundamentally different. Our results call into question our current understanding of the onset of order in active systems.

Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.

Plasticity of cancer invasion and metastasis depends on the ability of cancer cells to switch between collective and single-cell dissemination, controlled by cadherin-mediated cell-cell junctions. In clinical samples, E-cadherin-expressing and -deficient tumours both invade collectively and metastasize equally, implicating additional mechanisms controlling cell-cell cooperation and individualization. Here, using spatially defined organotypic culture, intravital microscopy of mammary tumours in mice and in silico modelling, we identify cell density regulation by three-dimensional tissue boundaries to physically control collective movement irrespective of the composition and stability of cell-cell junctions. Deregulation of adherens junctions by downregulation of E-cadherin and p120-catenin resulted in a transition from coordinated to uncoordinated collective movement along extracellular boundaries, whereas single-cell escape depended on locally free tissue space. These results indicate that cadherins and extracellular matrix confinement cooperate to determine unjamming transitions and stepwise epithelial fluidization towards, ultimately, cell individualization.

MicroRNA-222 Regulates Melanoma Plasticity.

Melanoma is one of the most aggressive and highly resistant tumors. Cell plasticity in melanoma is one of the main culprits behind its metastatic capabilities. The detailed molecular mechanisms controlling melanoma plasticity are still not completely understood. Here we combine mathematical models of phenotypic switching with experiments on IgR39 human melanoma cells to identify possible key targets to impair phenotypic switching. Our mathematical model shows that a cancer stem cell subpopulation within the tumor prevents phenotypic switching of the other cancer cells. Experiments reveal that hsa-mir-222 is a key factor enabling this process. Our results shed new light on melanoma plasticity, providing a potential target and guidance for therapeutic studies.

Unjamming of active rotators.

Active particle assemblies can exhibit a wide range of interesting dynamical phases depending on internal parameters such as density, adhesion strength or self-propulsion. Active self-rotations are rarely studied in this context, although they can be relevant for active matter systems, as we illustrate by analyzing the motion of Chlamydomonas reinhardtii algae under different experimental conditions. Inspired by this example, we simulate the dynamics of a system of interacting active disks endowed with active torques and self-propulsive forces. At low packing fractions, adhesion causes the formation of small rotating clusters, resembling those observed when algae are stressed. At higher densities, the model shows a jamming to unjamming transition promoted by active torques and hindered by adhesion. We also study the interplay between self-propulsion and self-rotation and derive a phase diagram. Our results yield a comprehensive picture of the dynamics of active rotators, providing useful guidance to interpret experimental results in cellular systems where rotations might play a role.

Chromatin and Cytoskeletal Tethering Determine Nuclear Morphology in Progerin-Expressing Cells.

The nuclear morphology of eukaryotic cells is determined by the interplay between the lamina forming the nuclear skeleton, the chromatin inside the nucleus, and the coupling with the cytoskeleton. Nuclear alterations are often associated with pathological conditions as in Hutchinson-Gilford progeria syndrome, in which a mutation in the lamin A gene yields an altered form of the protein, named progerin, and an aberrant nuclear shape. Here, we introduce an inducible cellular model of Hutchinson-Gilford progeria syndrome in HeLa cells in which increased progerin expression leads to alterations in the coupling of the lamin shell with cytoskeletal or chromatin tethers as well as with polycomb group proteins. Furthermore, our experiments show that progerin expression leads to enhanced nuclear shape fluctuations in response to cytoskeletal activity. To interpret the experimental results, we introduce a computational model of the cell nucleus that explicitly includes chromatin fibers, the nuclear shell, and coupling with the cytoskeleton. The model allows us to investigate how the geometrical organization of the chromatin-lamin tether affects nuclear morphology and shape fluctuations. In sum, our findings highlight the crucial role played by lamin-chromatin and lamin-cytoskeletal alterations in determining nuclear shape morphology and in affecting cellular functions and gene regulation.

Metamaterial architecture from a self-shaping carnivorous plant.

As meticulously observed and recorded by Darwin, the leaves of the carnivorous plant Drosera capensis L. slowly fold around insects trapped on their sticky surface in order to ensure their digestion. While the biochemical signaling driving leaf closure has been associated with plant growth hormones, how mechanical forces actuate the process is still unknown. Here, we combine experimental tests of leaf mechanics with quantitative measurements of the leaf microstructure and biochemistry to demonstrate that the closure mechanism is programmed into the cellular architecture of D. capensis leaves, which converts a homogeneous biochemical signal into an asymmetric response. Inspired by the leaf closure mechanism, we devise and test a mechanical metamaterial, which curls under homogeneous mechanical stimuli. This kind of metamaterial could find possible applications as a component in soft robotics and provides an example of bio-inspired design.

Ideal circle microswimmers in crowded media.

Microswimmers are exposed in nature to crowded environments and their transport properties depend in a subtle way on the interaction with obstacles. Here, we investigate a model for a single ideal circle swimmer exploring a two-dimensional disordered array of impenetrable obstacles. The microswimmer moves on circular orbits in the freely accessible space and follows the surface of an obstacle for a certain time upon collision. Depending on the obstacle density and the radius of the circular orbits, the microswimmer displays either long-range transport or is localized in a finite region. We show that there are transitions from two localized states to a diffusive state each driven by an underlying static percolation transition. We determine the non-equilibrium state diagram and calculate the mean-square displacements and diffusivities by computer simulations. Close to the transition lines transport becomes subdiffusive which is rationalized as a dynamic critical phenomenon.

From jamming to collective cell migration through a boundary induced transition.

Cell monolayers provide an interesting example of active matter, exhibiting a phase transition from flowing to jammed states as they age. Here we report experiments and numerical simulations illustrating how a jammed cellular layer rapidly reverts to a flowing state after a wound. Quantitative comparison between experiments and simulations shows that cells change their self-propulsion and alignment strength so that the system crosses a phase transition line, which we characterize by finite-size scaling in an active particle model. This wound-induced unjamming transition is found to occur generically in epithelial, endothelial and cancer cells.

Bursts of activity in collective cell migration.

Dense monolayers of living cells display intriguing relaxation dynamics, reminiscent of soft and glassy materials close to the jamming transition, and migrate collectively when space is available, as in wound healing or in cancer invasion. Here we show that collective cell migration occurs in bursts that are similar to those recorded in the propagation of cracks, fluid fronts in porous media, and ferromagnetic domain walls. In analogy with these systems, the distribution of activity bursts displays scaling laws that are universal in different cell types and for cells moving on different substrates. The main features of the invasion dynamics are quantitatively captured by a model of interacting active particles moving in a disordered landscape. Our results illustrate that collective motion of living cells is analogous to the corresponding dynamics in driven, but inanimate, systems.

Emergent vortices in populations of colloidal rollers.

Coherent vortical motion has been reported in a wide variety of populations including living organisms (bacteria, fishes, human crowds) and synthetic active matter (shaken grains, mixtures of biopolymers), yet a unified description of the formation and structure of this pattern remains lacking. Here we report the self-organization of motile colloids into a macroscopic steadily rotating vortex. Combining physical experiments and numerical simulations, we elucidate this collective behaviour. We demonstrate that the emergent-vortex structure lives on the verge of a phase separation, and single out the very constituents responsible for this state of polar active matter. Building on this observation, we establish a continuum theory and lay out a strong foundation for the description of vortical collective motion in a broad class of motile populations constrained by geometrical boundaries.

Diffusion, subdiffusion, and trapping of active particles in heterogeneous media.

We study the transport properties of a system of active particles moving at constant speed in a heterogeneous two-dimensional space. The spatial heterogeneity is modeled by a random distribution of obstacles, which the active particles avoid. Obstacle avoidance is characterized by the particle turning speed γ. We show, through simulations and analytical calculations, that the mean square displacement of particles exhibits two regimes as function of the density of obstacles ρ(o) and γ. We find that at low values of γ, particle motion is diffusive and characterized by a diffusion coefficient that displays a minimum at an intermediate obstacle density ρ(o). We observe that in high obstacle density regions and for large γ values, spontaneous trapping of active particles occurs. We show that such trapping leads to genuine subdiffusive motion of the active particles. We indicate how these findings can be used to fabricate a filter of active particles.

Optimal noise maximizes collective motion in heterogeneous media.

We study the effect of spatial heterogeneity on the collective motion of self-propelled particles (SPPs). The heterogeneity is modeled as a random distribution of either static or diffusive obstacles, which the SPPs avoid while trying to align their movements. We find that such obstacles have a dramatic effect on the collective dynamics of usual SPP models. In particular, we report about the existence of an optimal (angular) noise amplitude that maximizes collective motion. We also show that while at low obstacle densities the system exhibits long-range order, in strongly heterogeneous media collective motion is quasi-long-range and exists only for noise values in between two critical values, with the system being disordered at both large and low noise amplitudes. Since most real systems have spatial heterogeneities, the finding of an optimal noise intensity has immediate practical and fundamental implications for the design and evolution of collective motion strategies.