Abstract

Intratumoural heterogeneity contributes to local tumour recurrence and variable responses to radiotherapy in prostate cancer. Despite the multiclonal nature of the disease, tumour control probability for conventional treatment plans is modelled on the assumption that tumour cells in the target region respond identically and independently. Here, using tumour cell subpopulations with different radiation sensitivities from prostate tumour cell lines, we show that radiation resistant cells enhance the survival and radiation resistance of radio-sensitive cells in spheroids but not in monolayer culture. Mathematical modelling indicates that these phenotypic changes result from both competitive and antagonistic cellular interactions in spheroids. Interactions mediated by oxygen constraints define the spatial localisation of the cell populations in spheroids and in xenografts, while those mediated by paracrine signals further modify the microenvironment. Our results show new mechanisms of radiotherapy resistance mediated by cellular interactions and by the microenvironment.