Prostate cancer (PCa) is among the most commonly diagnosed cancers in men throughout westernized countries and is a leading cause of cancer-related mortality. Hormone deprivation therapy has been the backbone for PCa treatment by inhibiting androgen receptor (AR) signaling. However, resistance to this therapy is inevitable and men will progress to castrate-resistant prostate cancer (CRPC). While most patients will undergo resistant mechanisms involving the restoration of AR signaling and maintenance of an adenocarcinoma phenotype (CRPC-Ad), an increasingly accepted mechanism of resistance in approximately a quarter of tumors involves lineage plasticity. These tumors express low to absent AR levels, often demonstrating neuroendocrine features (CRPC-NE) and are indifferent to AR signaling. Further, genomic analysis reveals that CRPC-NE evolves from CRPC-Ad, but currently the molecular mechanisms underlying CRPC-NE are not completely understood. Work within my laboratory focuses on dissecting underlying genetic/epigenetic mechanisms of progression to aggressive CRPC-NE. For this work we utilize in vitro genetically modified human and mouse cell lines, 3D organoid cultures, in vivo genetically engineered mouse models, and clinical samples coupled with innovative technology including next generation sequencing approaches. Our overall goal is to identify these novel genomic/epigenomic mechanisms which will lead to discovery of biomarkers and therapeutic targets for clinical testing.