Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells

Abstract

The interplay between drug-sensitive and drug-resistant cancer cells has been observed to impact cell-to-cell interactions in experimental settings. However, the role that space plays in these interactions remains unclear. In this study, we develop mathematical models to investigate how spatial factors affect cell-to-cell competition between drug-sensitive and drug-resistant cancer cells in silico. We develop two baseline models to study cells from the epithelial FaDu cell line subjected to two drugs, specifically the ATR inhibitor ceralasertib and the PARP inhibitor olaparib, that target DNA damage response pathways. Our baseline models are: (1) a temporally resolved ordinary differential equation (ODE) model, and (2) a spatio-temporally resolved agent-based model (ABM). The models simulate cells in well-mixed and spatially structured cell systems, respectively. The ODE model is calibrated against in vitro data and is thereafter mapped onto the baseline ABM which, in turn, is extended to enable a simulation-based investigation on how spatial factors impact cell-to-cell competition. Simulation results from the extended ABMs demonstrate that the in silico treatment responses are simultaneously affected by: (i) the initial spatial cell configurations, (ii) the initial fraction of drug-resistant cells, (iii) the drugs to which cells express resistance, (iv) drug combinations, (v) drug doses, and (vi) the doubling time of drug-resistant cells compared to the doubling time of drug-sensitive cells. These results reveal that spatial structures of the simulated cancer cells affect both cell-to-cell interactions, and the impact that these interactions have on the ensuing population dynamics. This leads us to suggest that the role that space plays in cell-to-cell interactions should be further investigated and quantified in experimental settings.