Androgen receptor activation stabilizes a hybrid epithelial/mesenchymal phenotype in presence of Notch-Jagged signaling

Abstract

Metastasis is a key cause of mortality in cancer. It is driven majorly by clusters of circulating tumor cells which are often comprised of cells in a hybrid epithelial/mesenchymal (E/M) phenotype. Hybrid E/M phenotype has also been shown to be more tumor-initiating and therapy-resistant, but how cells maintain the hybrid E/M phenotype(s) remains an active area of investigation. Here, we develop a mathematical model that couples the intracellular dynamics of key players of Epithelial-Mesenchymal Transition (EMT) with the Androgen Receptor (AR), and cell-cell communication through Notch-Delta-Jagged signaling, in the context of prostate cancer. Our simulations show that AR can stabilize a hybrid E/M phenotype predominantly in the presence of Notch-Jagged, but not Notch-Delta, signaling. Implementing this model on a multi-cellular lattice, we observed that AR can alter the fraction of cells exhibiting a hybrid E/M and a mesenchymal phenotype. Finally, through analysis of transcriptomic and patient survival data, we found that the co-expression of AR and Jagged correlated with worse out-comes. Together, these results highlight the outcome of emergent dynamics between the Notch and AR signaling axis in promoting prostate cancer aggressiveness.