Intercepting YAP Activation in Prostate Cancer Blocks Neuroendocrine Progression

The emergence of the neuroendocrine phenotype in castration-resistant prostate cancer (CRPC) is associated with poor patient prognosis. Castration-induced death of fully differentiated, androgen-sensitive prostate cancer cells might foster interactions among rare androgen-independent, poorly differentiated cancer cells and the extracellular matrix (ECM) that promotes the development of neuroendocrine prostate cancer (NEPC). In this study, we investigated physical and molecular interactions between poorly differentiated prostate cancer cells with exocrine (PAC) or neuroendocrine features (PNE), which recapitulated preexisting human CRPC-like cells, and decellularized prostate ECM. Without androgens, PAC cells and prostate cancer-derived ECM promoted in vitro invasiveness of PNE cells by inducing integrin α2 upregulation and YAP activation, indicating a cell-to-cell and cell-to-matrix contact-driven process. Inhibition of RANK/RANKL and NF-κB prevented integrin α2 upregulation in PNE cells, and integrin α2β1 and YAP inhibition also reduced PNE invasiveness. Microenvironment-conditioned PNE cells showed YAP-dependent metastatic behavior in vivo, and YAP inhibition suppressed the development of NEPC and metastasis in castration-naïve mice and of neuroendocrine CRPC in transgenic mice with prostate cancer. Importantly, YAP inhibitors also restrained the growth of human CRPC organoids. These findings unveil mechanisms of NEPC development and implicate the integrin α2-YAP axis as a therapeutic target in patients with prostate cancer receiving androgen deprivation therapy. SIGNIFICANCE: Targeting signaling pathways activated by interactions between poorly differentiated neuroendocrine and exocrine prostate cancer cells and the surrounding ECM suppresses NEPC development and metastasis.