A mechanistic interpretation of mutation risk across biological scales

Abstract

The allometry of cancer risk in mammals is scale-specific, as the inter-specific, intra-specific, and inter-organ patterns in cancer risk scaling are distinct from each other. While cancer risk barely changes with increasing body sizes across species, larger conspecifics are known to be at a higher risk of cancer. Cancer risk trends with age and lifespan have likewise been documented in humans and other species. Nevertheless, mammals broadly share developmental features, and the twin processes of cell division and differentiation are central to developmental dynamics. In this study, we suppose that a better understanding of these processes across biological scales could lead to a clearer understanding of cancer risk allometries. We develop an agent-based model in which a cell compartment grows from one cell to a target size. We assess how developmental dynamics scale with compartment size and influence mutation accumulation. Our data identify specific regions of the parameter space where the accumulation of neutral mutations increases with cell number, while providing a mechanistic explanation for such behavior. The accumulation of non-neutral mutations reveals an interesting antagonism in cell fitness between mutation and differentiation, which could change the viability of a given developmental strategy. Our model is able to produce a wide range of trends in cancer risk allometries in different parts of its parameter space, reflecting the observed heterogeneity across biological scales. Our results provide a theoretical framework that allows us to elucidate the conditions of mutation-differentiation balance under which having more cells does lead to higher cancer risk, and importantly, the conditions under which it does not.