Cutting through the complexity of cell collectives.
ABSTRACT: Via strength in numbers, groups of cells can influence their environments in ways that individual cells cannot. Large-scale structural patterns and collective functions underpinning virulence, tumour growth and bacterial biofilm formation are emergent properties of coupled physical and biological processes within cell groups. Owing to the abundance of factors influencing cell group behaviour, deriving general principles about them is a daunting challenge. We argue that combining mechanistic theory with theoretical ecology and evolution provides a key strategy for clarifying how cell groups form, how they change in composition over time, and how they interact with their environments. Here, we review concepts that are critical for dissecting the complexity of cell collectives, including dimensionless parameter groups, individual-based modelling and evolutionary theory. We then use this hybrid modelling approach to provide an example analysis of the evolution of cooperative enzyme secretion in bacterial biofilms.
Project description:The mechanisms underlying collective migration are important for understanding development, wound healing, and tumor invasion. Here we focus on cell density to determine its role in collective migration. Our findings show that increasing cell density, as might be seen in cancer, transforms groups from broad collectives to small, narrow streams. Conversely, diminishing cell density, as might occur at a wound front, leads to large, broad collectives with a distinct leader-follower structure. Simulations identify force-sensitive contractility as a mediator of how density affects collectives, and guided by this prediction, we find that the baseline state of contractility can enhance or reduce organization. Finally, we test predictions from these data in an in vivo epithelium by using genetic manipulations to drive collective motion between predicted migratory phases. This work demonstrates how commonly altered cellular properties can prime groups of cells to adopt migration patterns that may be harnessed in health or exploited in disease.
Project description:Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas. Here we provide a comprehensive data set of the human HNSCC-associated fibroblast matrisome. Although much attention has been paid to the deposit of collagen, we identify oncofetal fibronectin (FN) as a major and obligate component of the matrix assembled by stromal fibroblasts from head and neck squamous cell carcinomas (HNSCC). FN overexpression in tumours from 435 patients corresponds to an independent unfavourable prognostic indicator. We show that migration of carcinoma collectives on fibrillar FN-rich matrices is achieved through ?v?6 and ?9?1 engagement, rather than ?5?1. Moreover, ?v?6-driven migration occurs independently of latent TGF-? activation and Smad-dependent signalling in tumour epithelial cells. These results provide insights into the adhesion-dependent events at the tumour-stroma interface that govern the collective mode of migration adopted by carcinoma cells to invade surrounding stroma in HNSCC.
Project description:A diversity of decision-making systems has been observed in animal collectives. In some species, choices depend on the differences of the numbers of animals that have chosen each of the available options, whereas in other species on the relative differences (a behavior known as Weber's law), or follow more complex rules. We here show that this diversity of decision systems corresponds to a single rule of decision making in collectives. We first obtained a decision rule based on Bayesian estimation that uses the information provided by the behaviors of the other individuals to improve the estimation of the structure of the world. We then tested this rule in decision experiments using zebrafish (Danio rerio), and in existing rich datasets of argentine ants (Linepithema humile) and sticklebacks (Gasterosteus aculeatus), showing that a unified model across species can quantitatively explain the diversity of decision systems. Further, these results show that the different counting systems used by animals, including humans, can emerge from the common principle of using social information to make good decisions.
Project description:Regulating the emergence of leaders is a central aspect of collective cell migration, but the underlying mechanisms remain ambiguous. Here we show that the selective emergence of leader cells at the epithelial wound-margin depends on the dynamics of the follower cells and is spatially limited by the length-scale of collective force transduction. Owing to the dynamic heterogeneity of the monolayer, cells behind the prospective leaders manifest locally increased traction and monolayer stresses much before these leaders display any phenotypic traits. Followers, in turn, pull on the future leaders to elect them to their fate. Once formed, the territory of a leader can extend only to the length up-to which forces are correlated, which is similar to the length up-to which leader cells can transmit forces. These findings provide mechanobiological insight into the hierarchy in cell collectives during epithelial wound healing.
Project description:We investigate low-dimensional examples of cyclic pursuit in a collective, wherein each agent employs a constant bearing (CB) steering law relative to exactly one other agent. For the case of three agents in the plane, we characterize relative equilibria and pure shape equilibria of associated closed-loop dynamics. Re-scaling time yields a reduction of phase space to two dimensions and effective tools for stability analysis. Study of bifurcation of a family of collinear equilibria dependent on a single CB control parameter reveals the presence of a rich collection of trajectories that are periodic in shape and undergo precession in physical space. For collectives in three dimensions, with an appropriate notion of CB pursuit strategy and corresponding steering law, the two-agent case proves to be explicitly integrable. These results suggest control schemes for small teams of mobile robotic agents engaged in area coverage tasks such as search and rescue, and raise interesting possibilities for behaviour in biological contexts.
Project description:The organization of cells, emerging from cell-cell interactions, can give rise to collective properties. These properties are adaptive when together cells can face environmental challenges that they separately cannot. One particular challenge that is important for microorganisms is migration. In this study, we show how flagellum-independent migration is driven by the division of labor of two cell types that appear during Bacillus subtilis sliding motility. Cell collectives organize themselves into bundles (called "van Gogh bundles") of tightly aligned cell chains that form filamentous loops at the colony edge. We show, by time-course microscopy, that these loops migrate by pushing themselves away from the colony. The formation of van Gogh bundles depends critically on the synergistic interaction of surfactin-producing and matrix-producing cells. We propose that surfactin-producing cells reduce the friction between cells and their substrate, thereby facilitating matrix-producing cells to form bundles. The folding properties of these bundles determine the rate of colony expansion. Our study illustrates how the simple organization of cells within a community can yield a strong ecological advantage. This is a key factor underlying the diverse origins of multicellularity.
Project description:BACKGROUND:Experimental evolution of microbes often involves a serial transfer protocol, where microbes are repeatedly diluted by transfer to a fresh medium, starting a new growth cycle. This has revealed that evolution can be remarkably reproducible, where microbes show parallel adaptations both on the level of the phenotype as well as the genotype. However, these studies also reveal a strong potential for divergent evolution, leading to diversity both between and within replicate populations. We here study how in silico evolved Virtual Microbe "wild types" (WTs) adapt to a serial transfer protocol to investigate generic evolutionary adaptations, and how these adaptations can be manifested by a variety of different mechanisms. RESULTS:We show that all WTs evolve to anticipate the regularity of the serial transfer protocol by adopting a fine-tuned balance of growth and survival. This anticipation is done by evolving either a high yield mode, or a high growth rate mode. We find that both modes of anticipation can be achieved by individual lineages and by collectives of microbes. Moreover, these different outcomes can be achieved with or without regulation, although the individual-based anticipation without regulation is less well adapted in the high growth rate mode. CONCLUSIONS:All our in silico WTs evolve to trust the hand that feeds by evolving to anticipate the periodicity of a serial transfer protocol, but can do so by evolving two distinct growth strategies. Furthermore, both these growth strategies can be accomplished by gene regulation, a variety of different polymorphisms, and combinations thereof. Our work reveals that, even under controlled conditions like those in the lab, it may not be possible to predict individual evolutionary trajectories, but repeated experiments may well result in only a limited number of possible outcomes.
Project description:Phosphorus intake in Europe is far above recommendations. We present baseline data from three human intervention studies between 2006 and 2014 regarding intake and excretion of phosphorus and calcium. All subjects documented their nutritional habits in weighed dietary records. Fasting blood samples were drawn, and feces and urine were quantitatively collected. Dietary phosphorus intake was estimated based on weighed dietary records and urine phosphorus excretions. Food sources were identified by allocation to defined food product groups. Average phosphorus consumption was 1338 mg/day and did not change from 2006 to 2014, while calcium intake decreased during this period (1150 to 895 mg/day). The main sources for phosphorus intake were bread/cereal products, milk/milk products and meat/meat products/sausage products and the main sources of calcium intake included milk/milk products/cheese, bread/cereal products and beverages. There was no difference between estimated phosphorus intake from the weighed dietary records and urine phosphorus excretion. In conclusion, we demonstrated constant phosphorus intakes far above the recommendations and decreasing calcium intakes below the recommendations in three German collectives from 2006 to 2014. Furthermore, we could show in case of usual intakes that an estimated phosphorus intake from urine phosphorus excretion is similar to the calculated intake from weighed dietary records.
Project description:Microbes engage in numerous social behaviours that are critical for survival and reproduction, and that require individuals to act as a collective. Various mechanisms ensure that collectives are composed of related, cooperating cells, thus allowing for the evolution and stability of these traits, and for selection to favour traits beneficial to the collective. Since microbes are difficult to observe directly, sociality in natural populations can instead be investigated using evolutionary genetic signatures, as social loci can be evolutionary hotspots. The budding yeast has been studied for over a century, yet little is known about its social behaviour in nature. Flo11 is a highly regulated cell adhesin required for most laboratory social phenotypes; studies suggest it may function in cell recognition and its heterogeneous expression may be adaptive for collectives such as biofilms. We investigated this locus and found positive selection in the areas implicated in cell-cell interaction, suggesting selection for kin discrimination. We also found balancing selection at an upstream activation site, suggesting selection on the level of variegated gene expression. Our results suggest this model yeast is surprisingly social in natural environments and is probably engaging in various forms of sociality. By using genomic data, this research provides a glimpse of otherwise unobservable interactions.
Project description:The demand for projections of the future distribution of biodiversity has triggered an upsurge in modelling at the crossroads between ecology and evolution. Despite the enthusiasm around these so-called biodiversity models, most approaches are still criticised for not integrating key processes known to shape species ranges and community structure. Developing an integrative modelling framework for biodiversity distribution promises to improve the reliability of predictions and to give a better understanding of the eco-evolutionary dynamics of species and communities under changing environments. In this article, we briefly review some eco-evolutionary processes and interplays among them, which are essential to provide reliable projections of species distributions and community structure. We identify gaps in theory, quantitative knowledge and data availability hampering the development of an integrated modelling framework. We argue that model development relying on a strong theoretical foundation is essential to inspire new models, manage complexity and maintain tractability. We support our argument with an example of a novel integrated model for species distribution modelling, derived from metapopulation theory, which accounts for abiotic constraints, dispersal, biotic interactions and evolution under changing environmental conditions. We hope such a perspective will motivate exciting and novel research, and challenge others to improve on our proposed approach.