Abstract
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.
Highlights
Cell competition is a fitness control mechanism in which less fit cells are eliminated from a tissue for optimal survival of the host (Vincent et al, 2013; Levayer and Moreno, 2013)
After calibrating the behaviour of winner and loser cells based on movies of pure cell populations, we show that we can replicate competition when the two distinct cell types are mixed and investigate the impact of each interaction and kinetic parameters on the outcome of mechanical cell competition
We find that mechanical competition appears to be controlled by the difference in homeostatic density between cell types, whereas biochemical competition is governed by tissue organisation
Summary
Cell competition is a fitness control mechanism in which less fit cells (the losers) are eliminated from a tissue for optimal survival of the host (Vincent et al, 2013; Levayer and Moreno, 2013). While there have been extensive population-scale studies of competition (Moreno et al, 2002; Wagstaff et al, 2016), the competitive strategies and their underlying mechanisms at the level of single cells remain poorly understood. Mechanical competition arises because loser cells are more sensitive to crowding than winners (Shraiman, 2005). By contrast, during biochemical competition, signalling occurs at the interface between cell types leading to apoptosis of loser cells only when in direct contact with winners (Moreno et al, 2002; Yamamoto et al, 2017).
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