The evolution of metapopulation dynamics and the number of stem cells in intestinal crypts and other tissue structures in multicellular bodies

Abstract

Carcinogenesis is a process of somatic evolution. Previous models of stem and transient amplifying cells in epithelial proliferating units like colonic crypts showed that intermediate numbers of stem cells in a crypt should optimally prevent progression to cancer. If a stem cell population is too small, it is easy for a mutator mutation to drift to fixation. If it is too large, it is easy for selection to drive cell fitness enhancing carcinogenic mutations to fixation. Here, we show that a multiscale microsimulation, that captures both within‐crypt and between‐crypt evolutionary dynamics, leads to a different conclusion. Epithelial tissues are metapopulations of crypts. We measured time to initiation of a neoplasm, implemented as inactivation of both alleles of a tumor suppressor gene. In our model, time to initiation is dependent on the spread of mutator clones in the crypts. The proportion of selectively beneficial and deleterious mutations in somatic cells is unknown and so was explored with a parameter. When the majority of non‐neutral mutations are deleterious, the fitness of mutator clones tends to decline. When crypts are maintained by few stem cells, intercrypt competition tends to remove crypts with fixed mutators. When there are many stem cells within a crypt, there is virtually no crypt turnover, but mutator clones are suppressed by within‐crypt competition. If the majority of non‐neutral mutations are beneficial to the clone, then these results are reversed and intermediate‐sized crypts provide the most protection against initiation. These results highlight the need to understand the dynamics of turnover and the mechanisms that control homeostasis, both at the level of stem cells within proliferative units and at the tissue level of competing proliferative units. Determining the distribution of fitness effects of somatic mutations will also be crucial to understanding the dynamics of tumor initiation and progression.

Aspirin’s effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study

“…Modified crypts of types APC-/- and KRAS + have been reported to undergo crypt fission; in other words, while the total population of a single crypt remains constant (even though it is populated by SCs that are fitter than the wild-type SCs), the crypt can undergo a doubling, thus increasing the total number of such modified crypts. The fission rates of different crypt types have been reported in the literature ( Paterson et al, 2020 ; Nicholson et al, 2018 ; Humphries et al, 2013 ; Baker et al, 2014 ) and are denoted by γ i ; we further denote by δ the death rate of crypts, see Birtwell et al, 2020 for the role of crypt turn-over. We model these dynamics by using the following system of ordinary differential equations: …”

The interface between ecology, evolution, and cancer: More than ever a relevant research direction for both oncologists and ecologists

“…Birtwell, Luebeck, Carlo, and Maley (in press, This volume) also proposed that to understand the dynamics of cancer initiation and progression, it is crucial to acknowledge that epithelia are divided into subpopulations of tissue stem cells along with the transient amplifying cells and differentiated cells that they produce. Therefore, a fundamental question in cancers like those affecting the intestinal tract is to determine how the crypt‐level metapopulation dynamics affect the accumulation of somatic mutations during carcinogenesis.…”