A computational model reveals that spatial localization of cancer stem cells increases radioresistance in tumorspheres

Abstract

Cancer stem cells (CSCs) exhibit increased resistance to radiotherapy, contributing to tumor recurrence and progression. While CSCs are known for their intrinsic resistance, the role of their spatial organization remains poorly understood. We extend a computational model of tumorsphere growth to investigate how the spatial distribution of CSCs influences radiation response. The model explicitly tracks cell lineages and spatial positions, revealing a preferential accumulation of CSCs in the spheroid interior. Because radiosensitivity increases with oxygen availability, and oxygen levels are lowest in the tumor core, this spatial organization confers a protective advantage to the CSC population. We find that this effect is negligible in small, well-oxygenated tumorspheres but becomes pronounced as growth leads to the emergence of hypoxic regions. To isolate the role of spatial structure, we compare these results with control simulations in which CSC positions are randomly reassigned. In these synthetic configurations, CSC survival under irradiation is markedly reduced, demonstrating that spatial localization is a key determinant of radioresistance. This effect persists even after the onset of central necrosis, suggesting that the "spatial niche" of CSCs is a critical target for improving therapeutic outcomes. Author SummaryCancer stem cells are known to survive radiotherapy better than other cancer cells, often leading to tumor recurrence. While this resistance is usually attributed to intrinsic biological differences between cells, in this study we show that their physical location within the tumor plays a critical and previously underestimated role. We developed a three-dimensional computer model that simulates the growth of a tumorsphere from a single cancer stem cell. Because oxygen levels influence how sensitive cells are to radiation, our model tracks the position of each cell and calculates the oxygen distribution. We found that cancer stem cells naturally accumulate in the poorly oxygenated spheroid core, where radiation is less effective. To confirm that this location directly causes their survival advantage, we performed a "digital experiment": We artificially redistributed the same cells randomly throughout the tumorsphere before applying simulated radiation. In this random configuration, cancer stem cell survival dropped significantly. Our results show that radioresistance is not only an intrinsic cell property, but also a consequence of the spatial structure of the tumor. This finding suggests that future therapies could be improved by targeting not only the stem cells themselves, but also the protective hypoxic niches where they reside.