Modeling Radiotherapy-Induced ECM Remodeling: Implications for Cellular Migration and Tumor Growth

Cancer progression is governed not only by the intrinsic properties of tumour cells but also by the microenvironment through which they migrate and grow. Here we develop a hierarchical modelling framework to investigate how extracellular matrix (ECM) structure and radiotherapy together shape cell trafficking and tumour evolution. In the first part of this work we model migration in confined environments by representing a single cell as a random walker on a percolation lattice, where occupied bonds mimic ECM fibres and obstacles represent steric barriers. We then extend the model to include radiation-induced remodelling of these fibres, enabling us to quantify how dynamic changes in ECM density and orientation influence motility. In the final stage we couple the percolation-based motility to a simple tumour growth module and implement a cytotoxic effect of radiotherapy on tumour cells. Using this multi-scale model we compare treatment schedules that vary in inter-fraction time and dosage. Our results indicate that intermediate regimens—either shorter inter-fraction intervals or lower per-fraction doses—can reduce tumour burden more effectively than extreme protocols by balancing cytotoxicity with the pro-migratory side effects of ECM remodelling. These findings underscore the importance of jointly considering matrix dynamics and radiation timing when designing radiotherapy schedules.