Non-genetic heterogeneity in prostate cancer through coupled dynamics of Androgen Receptor signalling, Epithelial-Mesenchymal Transition and Notch-Delta-Jagged signalling

Non-genetic heterogeneity is emerging to be a crucial factor underlying therapy resistance in multiple cancers. However, the design principles of regulatory networks underlying non-genetic heterogeneity in cancer remain poorly understood. Here, we investigate the coupled dynamics of feedback loops involving a) oscillations in androgen receptor (AR) signalling mediated through an intrinsically disordered protein PAGE4, b) multistability in epithelial-mesenchymal transition (EMT), and c) Notch-Delta-Jagged signalling mediated cell-cell communication, each of which can generate non-genetic heterogeneity through multistability and/or oscillations. Our results show how different coupling strengths between AR and EMT signalling can lead to possible bistability in levels of AR, which can be reinforced by Notch signalling. These results reveal how the emergent dynamics of coupling of oscillatory and multistable systems at an individual cell and a two-cell system and unravel various mechanisms through which AR signalling can generate non-genetic heterogeneity which can act as a barrier to most targeted therapies in the context of prostate cancer.