Abstract:
Cancers grow from clonal expansions of mutated somatic cells. These expansions are fueled by sequential mutation accumulation that may increase their proliferative capabilities and hence contribute to the positive selection of mutant cells. Ontogenetic strategies like increasing/decreasing the probabilities of asymmetric division and differentiation, DNA damage threshold etc. can affect the pattern and temporal dynamics of mutation accumulation. In a recently published agent-based model, Erten and Kokko take into account a set of such ontogenetic strategies and look at how some of these strategies may have evolved across a range of body sizes in order to optimize cancer risk. However, most models do not consider the fitness of different mutations and their role in shaping clonal evolution. We build an agent-based model based on Erten and Kokko 2020, but incorporate differential mutation fitness using distribution of fitness effects (DFEs). Our model illustrates the effect of different differentiation fluxes which affect the stem cell to non stem cell ratio. Systems with more divisions at lower differentiation stages have more stem cells than non stem cells and vice versa. These effects disappear with larger body sizes if we have sufficient differentiation rate. We also find that adding differential fitness filters disadvantageous mutations and thus reduces the rate of mutation accumulation. We find that contrary to prior expectations, reducing differentiation and having larger stem cell compartments may reduce rate of mutation accumulation. The effect of different DFEs on mutation accumulation dynamics remains to be explored.
