Should tissue structure suppress or amplify selection to minimize cancer risk?

Abstract

Background: It has been frequently argued that tissues evolved to suppress the accumulation of growth enhancing cancer inducing mutations. A prominent example is the hierarchical structure of tissues with high cell turnover, where a small number of tissue specific stem cells produces a large number of specialized progeny during multiple differentiation steps. Another well known mechanism is the spatial organization of stem cell populations and it is thought that this organization suppresses fitness enhancing mutations. However, in small populations the suppression of advantageous mutations typically also implies an increased accumulation of deleterious mutations. Thus, it becomes an important question whether the suppression of potentially few advantageous mutations outweighs the combined effects of many deleterious mutations. Results: We argue that the distribution of mutant fitness effects, e.g. the probability to hit a strong driver compared to many deleterious mutations, is crucial for the optimal organization of a cancer suppressing tissue architecture and should be taken into account in arguments for the evolution of such tissues. Conclusion: We show that for systems that are composed of few cells reflecting the typical organization of a stem cell niche, amplification or suppression of selection can arise from subtle changes in the architecture. Moreover, we discuss special tissue structures that can suppress most types of non-neutral mutations simultaneously. Reviewers: This article was reviewed by Benjamin Allen, Andreas Deutsch and Ignacio Rodriguez-Brenes. For the full reviews, please go to the Reviewers' comments section.

The evolutionary trade‐off between stem cell niche size, aging, and tumorigenesis

“…Certain spatially explicit models of stem cell niches, such as bowl-like network graphs and weighted graphs, result in less selective pressure on new mutations when compared to our model and lead to higher probabilities of fixation for deleterious mutations and lower probabilities of fixation for beneficial mutations (Hindersin, Werner, Dingli, & Traulsen, 2016). Thus, the estimates presented here of tumorigenesis may be higher and the estimates of tissue attrition may be lower when compared to more complex spatially explicit models.…”

“…We utilize an analytical approximation of cells replacing neighbors in a one‐dimensional ring, which is a proposed method of stem cell turnover (Lopez‐Garcia et al., ; Vermeulen et al., ), for the probability of fixation of new mutations within the stem cell niche. Certain spatially explicit models of stem cell niches, such as bowl‐like network graphs and weighted graphs, result in less selective pressure on new mutations when compared to our model and lead to higher probabilities of fixation for deleterious mutations and lower probabilities of fixation for beneficial mutations (Hindersin, Werner, Dingli, & Traulsen, ). Thus, the estimates presented here of tumorigenesis may be higher and the estimates of tissue attrition may be lower when compared to more complex spatially explicit models.…”

Fixation probabilities in graph-structured populations under weak selection

“…Spatial structure can also change the accumulation rate of neutral mutations, which do not affect fitness [14]. The effects of spatial structure on selection have consequences for microbial evolution [15], cancer [16][17][18][19][20], aging [19,20], and infectious disease [21].…”

A theory of evolutionary dynamics on any complex spatial structure

“…In the presence of clonal interference, lattice spatial structures also increase the waiting time for cancer, leading to a patchwork structure of non-uniformly sized clones (Martens et al, 2011). Hindersin et al (2016b) et al proposed topologies for small populations (∼12 cells) of stem cells at the intestinal crypt that could suppress evolution in both Birth-death and death-Birth processes;…”