The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease.

The development of de novo resistance is a major disadvantage in molecularly targeted therapies and is an open field of research. While most of the current understanding of the emergence of resistance is focused on cell-intrinsic mechanisms, we know the microenvironment plays a crucial role. Here, we focus on interactions between cancer cells and cancer associated fibroblasts (CAFs) to understand the local crosstalk facilitating residual disease. We model these spatial dynamics with a hybrid-discrete-continuum model. The stress response caused by treatment with molecular inhibitors can trigger a signal for assistance to which CAFs respond. Introducing breaks in treatment allows the microenvironment to normalise as the stress response subsides. We investigate how fluctuating environmental conditions shape the local crosstalk and, ultimately, the resulting residual disease. We find that treatment response depends on the complex interactions between the cancer cells and CAFs, modulated by local concentrations of drug and signalling molecules. With our model we investigate in silico how processes operating at different spatial and temporal scales result in a local environment that enables survival. This work provides a better understanding of the mechanisms that drive the creation of localised residual disease, crucial to informing the development of more effective treatment protocols.