Tissue evolution: Mechanical interplay of adhesion, pressure, and heterogeneity

Abstract

The evolution of various competing cell types in tissues, and the resulting persistent tissue population, is studied numerically and analytically in a particle-based model of active tissues. Mutations change the properties of cells in various ways, including their mechanical properties. Each mutation results in an advantage or disadvantage to grow in the competition between different cell types. While changes in signaling processes and biochemistry play an important role, we focus on changes in the mechanical properties by studying the result of variation of growth force and adhesive cross-interactions between cell types. For independent mutations of growth force and adhesion strength, the tissue evolves towards cell types with high growth force and low internal adhesion strength, as both increase the homeostatic pressure. Motivated by biological evidence, we postulate a coupling between both parameters, such that an increased growth force comes at the cost of a higher internal adhesion strength or vice versa. This tradeoff controls the evolution of the tissue, ranging from unidirectional evolution to very heterogeneous and dynamic populations. The special case of two competing cell types reveals three distinct parameter regimes: Two in which one cell type outcompetes the other, and one in which both cell types coexist in a highly mixed state. Interestingly, a single mutated cell alone suffices to reach the mixed state, while a finite mutation rate affects the results only weakly. Finally, the coupling between changes in growth force and adhesion strength reveals a mechanical explanation for the evolution towards intra-tumor heterogeneity, in which multiple species coexist even under a constant evolutianary pressure.\n\nAuthor summaryThe evolution of cell populations in growing tissues is due to mutations during cell division, and subsequent competition through various biochemical and mechanical factors. Cancer represents an example of such an evolution on a short time scale. It is a multistep process, where several mutations are needed in order for a tumor to develop and become malignant. Furthermore, cell types in a tumor are often found to be very heterogeneous. We employ computer simulations of a particle-based model of growing tissues to study the competition of various cell types through variations of the mechanical cell properties. Unconstraint evolution drives the tissue towards cell types with stronger growth force and reduced adhesion. However, growth force and adhesion are not independent. Motivated by biologcal evidence, we consider a tissue, where enhanced growth force is coupled to increased adhesion. In a regime around a balanced tradeoff, multiple cell types coexist in a tissue, providing a tentative explanation for tumor heterogeneity. The special case of a competition between two cell types facilitates the study of the underlying competition mechanism. For example, we find that the number fraction of mutated cells is nearly independent of the mutation rate km, as long as km is much smaller than the apoptosis rate ka.