Computational modelling of macrophage facilitated cancer metastasis using a cellular Potts model

Breast cancer mortality primarily results from metastatic dissemination. Macrophages are known to actively facilitate cancer cell invasion through the CSF-1/EGF paracrine signalling loop. This signalling loop involves tumour cells secreting colony-stimulating factor 1 (CSF-1) to recruit macrophages, which in turn release the epidermal growth factor (EGF) that promotes tumour cell migration and invasion. However, it remains incompletely understood how CSF-1/EGF chemical signalling cues and other related processes like chemotaxis, cell adhesion, and contact inhibition collectively give rise to the coordinated and persistent migration of tumour-macrophage aggregates required for invasion towards the endothelium. Here, a 2D cellular Potts model (CPM) is developed to investigate the spatiotemporal dynamics of how these coupled processes together govern tumour-macrophage aggregate formation and co-migration. Simulations show that metastasis depends on the combined influence of chemoattractant signalling, chemotactic responsiveness, physical cell-cell interactions, and directional migration rather than on any single process alone. In particular, changes in these processes can alter the collective mobility of tumour-macrophage aggregates, resulting in differences in cell displacement and migratory behaviour. Spatial variations in the CSF-1 and EGF fields generate cues for macrophage and cancer cell chemotaxis, with changes in their secretion and degradation rates influencing how these cues develop and persist across the simulation domain. Contact inhibition can attenuate chemotactic migration in dense cellular environments, while directional TAM migration contributes to tumour-macrophage movement towards the endothelium, with metastatic burden maximized at an intermediate directed-motion strength value. Overall, findings herein highlight the non-intuitive effects of changes in individual parameters and provide insight into the conditions that favour coordinated tumour-macrophage migration and invasion towards the endothelium. The framework herein can also help identify additional regulatory mechanisms that can be targeted through chemotherapy or immunotherapy strategies to limit metastasis.