Mathematical modelling reveals cellular dynamics within tumour spheroids

Author summary Tumour spheroids are an experimental assay used to characterise the dynamics and response to treatment of different cancer cell lines. Previous experiments have demonstrated that the localisation of tumour cell proliferation to the spheroid edge (due to the gradient formed by nutrient diffusing from the surrounding medium) causes cells to be pushed from the proliferative rim towards the nutrient-deficient necrotic core. This movement allows inert particles to infiltrate tumour spheroids. We use a hybrid agent-based model to reproduce this data. We show further how data from individual microbead trajectories can be used to infer the composition of simulated tumour spheroids, and to estimate model parameters pertaining to tumour cell proliferation rates and their responses to hypoxia. Since these measurements are possible using modern imaging techniques, this could motivate new experiments in which spheroid composition could be inferred by observing passive infiltration of inert particles. Tumour spheroids are widely used as anin vitroassay for characterising the dynamics and response to treatment of different cancer cell lines. Their popularity is largely due to the reproducible manner in which spheroids grow: the diffusion of nutrients and oxygen from the surrounding culture medium, and their consumption by tumour cells, causes proliferation to be localised at the spheroid boundary. As the spheroid grows, cells at the spheroid centre may become hypoxic and die, forming a necrotic core. The pressure created by the localisation of tumour cell proliferation and death generates an cellular flow of tumour cells from the spheroid rim towards its core. Experiments by Dorieet al. showed that this flow causes inert microspheres to infiltrate into tumour spheroids via advection from the spheroid surface, by adding microbeads to the surface of tumour spheroids and observing the distribution over time. We use an off-lattice hybrid agent-based model to re-assess these experiments and establish the extent to which the spatio-temporal data generated by microspheres can be used to infer kinetic parameters associated with the tumour spheroids that they infiltrate. Variation in these parameters, such as the rate of tumour cell proliferation or sensitivity to hypoxia, can produce spheroids with similar bulk growth dynamics but differing internal compositions (the proportion of the tumour which is proliferating, hypoxic/quiescent and necrotic/nutrient-deficient). We use this model to show that the types of experiment conducted by Dorieet al. could be used to infer spheroid composition and parameters associated with tumour cell lines such as their sensitivity to hypoxia or average rate of proliferation, and note that these observations cannot be conducted within previous continuum models of microbead infiltration into tumour spheroids as they rely on resolving the trajectories of individual microbeads.