Stochastic modelling of prostate progenitor architecture

Prostate cancer is a significant global health concern. In the past decade, advances in mathematical models of the disease have led to clinical trials for new therapeutic protocols. However, much of the structure of the prostate and its constituent cell types remains unclear: observations of phenotypic switching between basal and luminal cells, as well as intermediate cell types between them, make classifying the components of the prostate an ongoing challenge. Importantly, a tumour's cell of origin seems to play a role in the aggressiveness and genetic heterogeneity of the cancer. Here we represent the emergence of a tumour by a fit mutant arising amongst healthy, wild-type cells, and we measure the cancer emergence probability and tumour latency by stochastically simulating the system. Taking a compartment model approach, we label cells based on their phenotype and allow for some phenotypic switching between them. We use this to investigate how different structures between cell types impact the emergence and treatment of prostate cancer. We posit that under-regulation of the luminal compartment allows for the explosive population growth associated with cancer. Also, we find that tumours arising in the basal compartment require more time to spread but are more strongly embedded within the prostate, explaining the longer latency and higher aggressiveness and persistence associated with these tumours. Interestingly, the inclusion of a hybrid compartment does not qualitatively change the observations, raising questions as to what mechanistic role intermediate phenotypes play in prostate cancer emergence, if any. Our model contributes to dissecting the relationship between prostate structure and outcomes for cancers arising therein.