Cell-scale biophysical determinants of cell competition in epithelia.

How cells with different genetic makeups compete in tissues is an outstanding question in developmental biology and cancer research. Studies in recent years have revealed that cell competition can either be driven by short-range biochemical signalling or by long-range mechanical stresses in the tissue. To date, cell competition has generally been characterised at the population scale, leaving the single-cell-level mechanisms of competition elusive. Here, we use high time-resolution experimental data to construct a multi-scale agent-based model for epithelial cell competition and use it to gain a conceptual understanding of the cellular factors that governs competition in cell populations within tissues. We find that a key determinant of mechanical competition is the difference in homeostatic density between winners and losers, while differences in growth rates and tissue organisation do not affect competition end result. In contrast, the outcome and kinetics of biochemical competition is strongly influenced by local tissue organisation. Indeed, when loser cells are homogenously mixed with winners at the onset of competition, they are eradicated; however, when they are spatially separated, winner and loser cells coexist for long times. These findings suggest distinct biophysical origins for mechanical and biochemical modes of cell competition.

Single-cell approaches to cell competition: High-throughput imaging, machine learning and simulations.

Cell competition is a quality control mechanism in tissues that results in the elimination of less fit cells. Over the past decade, the phenomenon of cell competition has been identified in many physiological and pathological contexts, driven either by biochemical signaling or by mechanical forces within the tissue. In both cases, competition has generally been characterized based on the elimination of loser cells at the population level, but significantly less attention has been focused on determining how single-cell dynamics and interactions regulate population-wide changes. In this review, we describe quantitative strategies and outline the outstanding challenges in understanding the single cell rules governing tissue-scale competition dynamics. We propose quantitative metrics to characterize single cell behaviors in competition and use them to distinguish the types and outcomes of competition. We describe how such metrics can be measured experimentally using a novel combination of high-throughput imaging and machine learning algorithms. We outline the experimental challenges to quantify cell fate dynamics with high-statistical precision, and describe the utility of computational modeling in testing hypotheses not easily accessible in experiments. In particular, cell-based modeling approaches that combine mechanical interaction of cells with decision-making rules for cell fate choices provide a powerful framework to understand and reverse-engineer the diverse rules of cell competition.

Local cellular neighborhood controls proliferation in cell competition.

Cell competition is a quality-control mechanism through which tissues eliminate unfit cells. Cell competition can result from short-range biochemical inductions or long-range mechanical cues. However, little is known about how cell-scale interactions give rise to population shifts in tissues, due to the lack of experimental and computational tools to efficiently characterize interactions at the single-cell level. Here, we address these challenges by combining long-term automated microscopy with deep-learning image analysis to decipher how single-cell behavior determines tissue makeup during competition. Using our high-throughput analysis pipeline, we show that competitive interactions between MDCK wild-type cells and cells depleted of the polarity protein scribble are governed by differential sensitivity to local density and the cell type of each cell's neighbors. We find that local density has a dramatic effect on the rate of division and apoptosis under competitive conditions. Strikingly, our analysis reveals that proliferation of the winner cells is up-regulated in neighborhoods mostly populated by loser cells. These data suggest that tissue-scale population shifts are strongly affected by cellular-scale tissue organization. We present a quantitative mathematical model that demonstrates the effect of neighbor cell-type dependence of apoptosis and division in determining the fitness of competing cell lines.