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.

The Response of Triple-Negative Breast Cancer to Neoadjuvant Chemotherapy and the Epithelial-Mesenchymal Transition.

It would be highly desirable to find prognostic and predictive markers for triple-negative breast cancer (TNBC), a strongly heterogeneous and invasive breast cancer subtype often characterized by a high recurrence rate and a poor outcome. Here, we investigated the prognostic and predictive capabilities of ARIADNE, a recently developed transcriptomic test focusing on the epithelial-mesenchymal transition. We first compared the stratification of TNBC patients obtained by ARIADNE with that based on other common pathological indicators, such as grade, stage and nodal status, and found that ARIADNE was more effective than the other methods in dividing patients into groups with different disease-free survival statistics. Next, we considered the response to neoadjuvant chemotherapy and found that the classification provided by ARIADNE led to statistically significant differences in the rates of pathological complete response within the groups.

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.

Topography of epithelial-mesenchymal plasticity.

The transition between epithelial and mesenchymal states has fundamental importance for embryonic development, stem cell reprogramming, and cancer progression. Here, we construct a topographic map underlying epithelial-mesenchymal transitions using a combination of numerical simulations of a Boolean network model and the analysis of bulk and single-cell gene expression data. The map reveals a multitude of metastable hybrid phenotypic states, separating stable epithelial and mesenchymal states, and is reminiscent of the free energy measured in glassy materials and disordered solids. Our work not only elucidates the nature of hybrid mesenchymal/epithelial states but also provides a general strategy to construct a topographic representation of phenotypic plasticity from gene expression data using statistical physics methods.

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.

Universal Low-Frequency Vibrational Modes in Silica Glasses.

It was recently shown that different simple models of glass formers with binary interactions define a universality class in terms of the density of states of their quasilocalized low-frequency modes. Explicitly, once the hybridization with standard Debye (extended) modes is avoided, a number of such models exhibit a universal density of states, depending on the mode frequencies as D(ω)∼ω^{4}. It is unknown, however, how wide this universality class is, and whether it also pertains to more realistic models of glass formers. To address this issue we present analysis of the quasilocalized modes in silica, a network glass that has both binary and ternary interactions. We conclude that in three dimensions silica exhibits the very same frequency dependence at low frequencies, suggesting that this universal form is a generic consequence of amorphous glassiness.

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.

Explaining the dynamics of tumor aggressiveness: At the crossroads between biology, artificial intelligence and complex systems.

Facing metastasis is the most pressing challenge of cancer research. In this review, we discuss recent advances in understanding phenotypic plasticity of cancer cells, highlighting the kinetics of cancer stem cell and the role of the epithelial mesenchymal transition for metastasis. It appears that the tumor micro-environment plays a crucial role in triggering phenotypic transitions, as we illustrate discussing the challenges posed by macrophages and cancer associated fibroblasts. To disentangle the complexity of environmentally induced phenotypic transitions, there is a growing need for novel advanced algorithms as those proposed in our recent work combining single cell data analysis and numerical simulations of gene regulatory networks. We conclude discussing recent developments in artificial intelligence and its applications to personalized cancer treatment.

Statistical Features of Collective Cell Migration.

We discuss recent advances in interpreting the collective dynamics of cellular assemblies using ideas and tools coming from the statistical physics of materials. Experimental observations suggest analogies between the collective motion of cell monolayers and the jamming of soft materials. Granular media, emulsions and other soft materials display transitions between fluid-like and solid-like behavior as control parameters, such as temperature, density and stress, are changed. A similar jamming transition has been observed in the relaxation of epithelial cell monolayers. In this case, the associated unjamming transition, in which cells migrate collectively, is linked to a variety of biochemical and biophysical factors. In this framework, recent works show that wound healing induce monolayer fluidization with collective migration fronts moving in an avalanche-like behavior reminiscent of intermittent front propagation in materials such as domain walls in magnets, cracks in disordered media or flux lines in superconductors. Finally, we review the ability of discrete models of cell migration, from interacting active particles to vertex and Voronoi models, to simulate the statistical properties observed experimentally.

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.

Damage Accumulation in Silica Glass Nanofibers.

The origin of the brittle-to-ductile transition, experimentally observed in amorphous silica nanofibers as the sample size is reduced, is still debated. Here we investigate the issue by extensive molecular dynamics simulations at low and room temperatures for a broad range of sample sizes, with open and periodic boundary conditions. Our results show that small sample-size enhanced ductility is primarily due to diffuse damage accumulation, that for larger samples leads to brittle catastrophic failure. Surface effects such as boundary fluidization contribute to ductility at room temperature by promoting necking, but are not the main driver of the transition. Our results suggest that the experimentally observed size-induced ductility of silica nanofibers is a manifestation of finite-size criticality, as expected in general for quasi-brittle disordered networks.

Strain Modulation of Graphene by Nanoscale Substrate Curvatures: A Molecular View.

Spatially nonuniform strain is important for engineering the pseudomagnetic field and band structure of graphene. Despite the wide interest in strain engineering, there is still a lack of control on device-compatible strain patterns due to the limited understanding of the structure-strain relationship. Here, we study the effect of substrate corrugation and curvature on the strain profiles of graphene via combined experimental and theoretical studies of a model system: graphene on closely packed SiO2 nanospheres with different diameters (20-200 nm). Experimentally, via quantitative Raman analysis, we observe partial adhesion and wrinkle features and find that smaller nanospheres induce larger tensile strain in graphene; theoretically, molecular dynamics simulations confirm the same microscopic structure and size dependence of strain and reveal that a larger strain is caused by a stronger, inhomogeneous interaction force between smaller nanospheres and graphene. This molecular-level understanding of the strain mechanism is important for strain engineering of graphene and other two-dimensional materials.

Complexity in cancer stem cells and tumor evolution: Toward precision medicine.

In this review, we discuss recent advances on the plasticity of cancer stem cells and highlight their relevance to understand the metastatic process and to guide therapeutic interventions. Recent results suggest that the strict hierarchical structure of cancer cell populations advocated by the cancer stem cell model must be reconsidered since the depletion of cancer stem cells leads the other tumor cells to switch back into the cancer stem cell phenotype. This plasticity has important implications for metastasis since migrating cells do not need to be cancer stem cells in order to seed a metastasis. We also discuss the important role of the immune system and the microenvironment in modulating phenotypic switching and suggest possible avenues to exploit our understanding of this process to develop an effective strategy for precision medicine.

Impact of the cross-talk between circular and messenger RNAs on cell regulation.

Circular RNAs (circRNA) are non-coding RNAs characterized by a closed-loop structure providing increased stability and enhancing their ability to compete with messenger RNAs (mRNA) for microRNA (miRNA) binding. An important open question is if circRNA plays a physiological role in the cells regulating critical cellular functions. We address this question with a combination of theoretical modeling and experimental analysis. Theoretically, we investigated two possible scenarios, one in which circRNAs act as sponges for miRNAs but there is no other relation between the two RNAs and the other one where circRNAs are co-generated with their corresponding mRNAs. We thus compared the results with data reporting the level of circRNAs (ZEB1, CANCX, ABCC1) modulating specific miRNAs in 27 cell lines. Due to the high stability of circRNAs, we show that a miRNA mediated cross-talk between circRNA and mRNA appears for a broad range of physiological parameters. This confirms the relevance of circRNAs in cell regulation, suggesting that they could be used as biomarkers.

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.

Quasi-periodic events in crystal plasticity and the self-organized avalanche oscillator.

When external stresses in a system--physical, social or virtual--are relieved through impulsive events, it is natural to focus on the attributes of these avalanches. However, during the quiescent periods between them, stresses may be relieved through competing processes, such as slowly flowing water between earthquakes or thermally activated dislocation flow between plastic bursts in crystals. Such smooth responses can in turn have marked effects on the avalanche properties. Here we report an experimental investigation of slowly compressed nickel microcrystals, covering three orders of magnitude in nominal strain rate, in which we observe unconventional quasi-periodic avalanche bursts and higher critical exponents as the strain rate is decreased. Our experiments are faithfully reproduced by analytic and computational dislocation avalanche modelling that we have extended to incorporate dislocation relaxation, revealing the emergence of the self-organized avalanche oscillator: a novel critical state exhibiting oscillatory approaches towards a depinning critical point. This theory suggests that whenever avalanches compete with slow relaxation--in settings ranging from crystal microplasticity to earthquakes--dynamical quasi-periodic scale invariance ought to emerge.

Deformation and failure of curved colloidal crystal shells.

Designing and controlling particle self-assembly into robust and reliable high-performance smart materials often involves crystalline ordering in curved spaces. Examples include carbon allotropes like graphene, synthetic materials such as colloidosomes, or biological systems like lipid membranes, solid domains on vesicles, or viral capsids. Despite the relevance of these structures, the irreversible deformation and failure of curved crystals is still mostly unexplored. Here, we report simulation results of the mechanical deformation of colloidal crystalline shells that illustrate the subtle role played by geometrically necessary topological defects in controlling plastic yielding and failure. We observe plastic deformation attributable to the migration and reorientation of grain boundary scars, a collective process assisted by the intermittent proliferation of disclination pairs or abrupt structural failure induced by crack nucleating at defects. Our results provide general guiding principles to optimize the structural and mechanical stability of curved colloidal crystals.

Excitation Spectra in Crystal Plasticity.

Plastically deforming crystals exhibit scale-free fluctuations that are similar to those observed in driven disordered elastic systems close to depinning, but the nature of the yielding critical point is still debated. Here, we study the marginal stability of ensembles of dislocations and compute their excitation spectrum in two and three dimensions. Our results show the presence of a singularity in the distribution of excitation stresses, i.e., the stress needed to make a localized region unstable, that is remarkably similar to the one measured in amorphous plasticity and spin glasses. These results allow us to understand recent observations of extended criticality in bursty crystal plasticity and explain how they originate from the presence of a pseudogap in the excitation spectrum.

Direct Observation of Percolation in the Yielding Transition of Colloidal Glasses.

When strained beyond the linear regime, soft colloidal glasses yield to steady-state plastic flow in a way that is similar to the deformation of conventional amorphous solids. Because of the much larger size of the colloidal particles with respect to the atoms comprising an amorphous solid, colloidal glasses allow us to obtain microscopic insight into the nature of the yielding transition, as we illustrate here combining experiments, atomistic simulations, and mesoscopic modeling. Our results unanimously show growing clusters of nonaffine deformation percolating at yielding. In agreement with percolation theory, the spanning cluster is fractal with a fractal dimension d_{f}≃2, and the correlation length diverges upon approaching the critical yield strain. These results indicate that percolation of highly nonaffine particles is the hallmark of the yielding transition in disordered glassy systems.

Modeling mechanical control of spindle orientation of intestinal crypt stem cells.

Tissue development requires a control over the sequence of symmetric and asymmetric stem cell divisions to obtain the specific numbers of differentiated cells populating the tissue and stem cells residing in the niche. A good experimental model to study this process is the mouse intestinal crypt development, where it has been shown that stem cells follow an optimal strategy in which asymmetric division occurs only after all symmetric divisions have taken place to reach a fixed number of cells in the niche in the shortest time. Here we introduce a model of stem cell division that is able to explain the experimentally observed stem cell population dynamics by the effect of mechanical forces acting on the spindle. We also observe that the mechanically induced strategy for development is sub-optimal and crucially depends on the stiffness of the spindle. These findings highlight the crucial importance of mechanical forces for the development and maintenance of the intestinal crypt.