Abstract
Abstract
Radiotherapy remains one of the most widely used cancer treatments. However, optimizing its effectiveness requires a deeper understanding of the tumor architecture and its influence on radiation response. Three-dimensional spheroid cultures offer a more physiologically relevant model than traditional 2D assays, and their integration with in silico techniques enable the simulation of both growth dynamics and radiobiological response across multiple scales. In this study, we developed a multi-scale in silico framework capable of simulating tumor spheroid growth, using a Cellular Potts Model, and transferring that information to OpenTOPAS to simulate irradiation with any given particle type. The dose deposited at each cell was used to determine cell fate via a Two-Lesion Kinetic Model (TLKM), which accounts for cellular oxygen concentration, the number of radiation-induced double-strand breaks, their type (simple or complex), and their origin (direct or indirect). The model was applied to two rectal cancer cell lines (SW837 and SW1463) subjected to a short-course radiotherapy regimen of 5 Gy/fraction over 5 consecutive days, mimicking the treatment protocol used in rectal cancer patients. The model successfully captured key biological phenomena, including reoxygenation of hypoxic cells following each fraction and the persistence of necrotic cells due to limited clearance mechanisms. To our knowledge, this is also the first practical application of the oxygen fixation parameter within the TLKM. This framework provides a flexible platform for investigating alternative treatment regimens, combination therapies, and particle-based modalities. Expanding the experimental dataset, particularly with spatially resolved measurements of proliferative, hypoxic, and necrotic zones, will be essential to further constrain and validate the model. Incorporating subcellular damage mechanisms and explicit dose-rate effects into the TLKM formulation represents key directions for future development.