PROJECT SUMMARY Potent antagonists of androgen and androgen receptor (AR) signaling have revolutionized the treatment of recurrent prostate cancer (PrCa). Despite initial responses, all patients eventually become resistant to treatment, but in approximately 20% of the cases, and perhaps more, the disease evolves in response to therapy to a new, rapidly progressing and diffusely metastatic neuroendocrine prostate cancer (NEPC), with a life expectancy of 7 months or less. NEPC is not merely a case of treatment resistance. Instead, it is the result of the extraordinary plasticity of tumor cells that adapt to the evolutionary pressure imposed by drug treatment to change lineage specification, lose AR dependence, modulate transcriptional networks, and acquire new traits of heightened cell invasion and metastasis. Fully integrated with the other components of this Program, Project 2 has now identified two novel determinants of NEPC plasticity that drive metastatic disease. We found that exposure to androgen-deprivation therapy triggers unrestrained transcription and increased production of the proinflammatory cytokine, interleukin-1β (IL-1β), resulting in increased PrCa motility, skeletal metastases and reprogramming of the bone metastatic microenvironment, in vivo. In addition, these NEPC metastases exhibit persistent mitochondrial dysfunction due to reduced levels of the organelle scaffolding protein, Mic60. In turn, these Mic60-low mitochondria become multifunctional signaling hubs in NEPC: they activate a pro- survival endoplasmic reticulum (ER) stress response, upregulate an immune-inflammatory transcriptome, and reprogram metabolism to fuel increased tumor cell invasion and metastasis. Pharmacologic or genetic targeting of this pathway restores tumor cell killing and suppresses NEPC, in vivo. Therefore, the hypothesis that deregulated IL-1β production and Mic60-low mitochondrial signaling are novel determinants of therapy-induced metastatic NEPC and actionable thera