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 outcomes. Together, these results highlight the outcome of emergent dynamics between the Notch and AR signaling axis in promoting prostate cancer aggressiveness.
Guha et al. (Tue,) studied this question.