RESUMEN
Cancer cell populations comprise phenotypes distributed among the epithelial-mesenchymal (E-M) spectrum. However, it remains unclear which population-level processes give rise to the observed experimental distribution and dynamical changes in E-M heterogeneity, including (1) differential growth, (2) cell-state switching, and (3) population density-dependent growth or state-transition rates. Here, we analyze the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that, while cell-state transition is necessary to reproduce experimental observations of dynamical changes in E-M fractions, including density-dependent growth interactions (cooperation or suppression) better explains the data. Further, our models predict that treatment of HCC38 cells with transforming growth factor ß (TGF-ß) signaling and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/3) inhibitors enhances the rate of mesenchymal-epithelial transition (MET) instead of lowering that of E-M transition (EMT). Overall, our study identifies the population-level processes shaping the dynamics of spontaneous E-M heterogeneity in breast cancer cells.
RESUMEN
Evolution during range expansions shapes the fate of many biological systems including tumours, microbial communities, and invasive species. A fundamental process of interest is the selective sweep, in which an advantageous mutation evades clonal interference and spreads through the population to fixation. However, most theoretical investigations of selective sweeps have assumed constant population size or have ignored spatial structure. Here we use mathematical modelling and analysis to investigate selective sweep probabilities in populations that spread outwards as they evolve. In the case of constant radial expansion speed, we derive probability distributions for the arrival time and location of the first surviving mutant and hence find surprisingly simple approximate and exact expressions for selective sweep probabilities in one, two and three dimensions, which are independent of mutation rate. Namely, the selective sweep probability is approximately 1-cwt/cmd, where cwt and cm are the wildtype and mutant radial expansion speeds, and d the spatial dimension. Using agent-based simulations, we show that our analytical results accurately predict selective sweep frequencies in the two-dimensional spatial Moran process. We further compare our results with those obtained for alternative growth models. Parameterizing our model for human tumours, we find that selective sweeps are predicted to be rare except during very early solid tumour growth, thus providing a general, pan-cancer explanation for findings from recent sequencing studies.