Modelling the distinct roles of epithelial and stromal androgen receptor in the regulation of prostate epithelial dynamics.

Abstract

The prostate is an androgen-responsive organ, but the complex cellular and molecular interactions that mediate these responses remain incompletely defined. Here, I synthesise the existing literature to derive a simple conceptual framework describing the androgen-dependent regulation of prostate epithelial dynamics. In this framework, epithelial androgen receptor (AR) cell-autonomously controls luminal cell height, whereas stromal AR regulates the synthesis of growth factors that promote luminal cell survival and proliferation. With the additional aid of a reanalysis of single-cell RNA-seq data, I also propose that insulin-like growth factor 1 (IGF1) functions as a key androgen-dependent growth factor coordinating stromal-to-epithelial paracrine communication. A novel mathematical model based on this framework was able to quantitatively fit experimental data describing prostate regression and regeneration. Model analysis demonstrates how the luminal cell population can maintain a stable equilibrium size via competition for and degradation of stroma-derived IGF1 and how this population size can be controlled by androgen levels, without a requirement for distinct luminal cell subsets. Moreover, model simulations were able to qualitatively recapitulate experimental observations in inflammatory and cancerous states, thereby providing insights into potential disease mechanisms. This simple model could therefore serve as a foundation for more comprehensive modelling of both the healthy and diseased prostate.