Cell-scale biophysical determinants of cell competition in epithelia

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.

Levels of p53 expression determine the competitive ability of embryonic stem cells during the onset of differentiation

“…More sophisticated agent-based multi-scale models can be used to simulate more specific cell and tissue morphologies, such as competition during the transition to congruence. An example of such models was used in (Gradeci et al, 2021) using automatic annotation of movies of co-cultured wild-type and polarity deficient MDCK cells lasting up to 4 days, providing extensive input on the behaviour of wild-type and mutant cells. Their modelling identified that cell density and stiffness is sufficient to account for the apoptotic elimination of loser cells during mechanical competition.…”

A Stiff Extracellular Matrix Favors the Mechanical Cell Competition that Leads to Extrusion of Bacterially-Infected Epithelial Cells

“…Given that ECM stiffness increases in certain pathologies including fibrotic diseases, cancer and inflammatory bowel diseases (IBD) ( Lampi and Reinhart-King, 2018 ; Onfroy-Roy et al, 2020 ), it remains still an open question whether varying ECM stiffness would promote or limit infected cell extrusion and, if so, what would be the physical and molecular mechanisms involved. Interestingly, Gradeci et al, showed that changes in the ratio of winner-to-loser cell stiffness altered the kinetics of cell competition between wild-type MDCK cells and cells depleted for the polarity protein scribble, although ECM stiffness was not addressed in this study ( Gradeci et al, 2021 ). Another study on competition between wild-type cells and oncogenically-transformed ones did show that increasing ECM stiffness attenuates extrusion of transformed cells by tuning the dynamic localization of filamin, an important F-actin crosslinking protein ( Pothapragada et al, 2022 ).…”

“…Cell competition refers to the process whereby less fit cells, often denoted “losers”, are sensed and eliminated by more fit neighboring cells, accordingly referred to as “winners” ( Gradeci et al, 2021 ). This competition between losers and winners is essential for tissue homeostasis but it also emerges during tissue development and can play a role in various pathologies including tumor development ( Meyer et al, 2014 ; Moreno et al, 2019 ).…”

A competitive advantage through fast dead matter elimination in confined cellular aggregates

“…Evidence for homeostatic cell density as a predictor of fitness can be found in both experiments and simulations [1,16,38,39] and indeed homeostatic density has already been suggested as a competition driver, but only in a very limited sense: one that attributes fitness to a species-dependent threshold density above which apoptosis is triggered [40][41][42]. The quite intuitive reasoning for the homeostatic density driving the competition in that specific case is that the 'loser' species can be above the threshold and diminishes while the 'winner' species is still below its own apoptosis threshold and prospers.…”

“…Here, on the other hand, we allow for a more general relationship between the death and division rates that still supports homeostasis. Another distinction is that, in [40][41][42], division and death rates were considered to depend directly on the density of growing cells, while here we consider these to depend on pressure as seen experimentally in many systems including in epithelia [31], tumours [43,44], morphogenesis [2], yeast [30] and bacteria [45]. When proliferation and/or removal rates depend on pressure, they are affected by the production of all load-bearing matter in the confined system, and not just by the active growing cells.…”