Growth, proliferation, and the pursuit of fitness: How cell-scale forces shape competitive population dynamics

Cell competition is a fitness control mechanism in tissues, where less fit cells are eliminated to maintain tissue homeostasis. Two primary mechanisms of cell elimination have been identified in cell competition studies: contact-dependent cell death and mechanical compression-driven apoptosis. While both occur in tissues, their combined impact on population dynamics is unclear. Here we develop a cell-based computational model to study competition between two cell types with differing physical properties. We incorporate probabilistic rules governing cell growth, division, and elimination, while also taking into account their feedback with tissue mechanics. To both validate our model and acting as a necessary stepping stone to simulate cell competition, we first begin with a study of the mechanics of a growing tissue composed of a single cell type. In this effort we sought to predict how tissue confinement influences cell size and proliferation dynamics, and how single-cell physical properties influence the spatiotemporal patterns of tissue growth. We show that the cell size threshold at G1/S transition governs the homeostatic cell density and tissue turnover rate, while the mechanical state of the tissue governs the dynamics of tissue growth. Furthermore, by tuning cellular elasticity and contact inhibition of proliferation we can regulate the emergent patterns of cell proliferation, ranging from uniform growth at low contact inhibition to localized growth at higher contact inhibition. With this validation of our model for a single cell type, we move on to explore how differences in physical traits between cell types influence competitive interactions. Our findings show that differences in cell compressibility alone can drive mechanical competition, with stiffer cells out competing softer ones in otherwise identical populations. Surprisingly, mutations that reduce cell stiffness, combined with decreased contact inhibition of proliferation, can create a “soft” super-competitive mutant. We demonstrate that changes in apoptosis sensitivity, cell ad?hesion, and cell size significantly affect growth potential and susceptibility to apoptosis. Furthermore, mutant cell colonies require a critical colony size, dependent on cell compressibility, to overtake the surrounding wild-type tissue. For colonies below the critical size, the elimination process is stochastic, driven by a protrusive finger-like instability in the interface between two cells that promote invasion of the super-competitors.