LAUSR

INTRODUCTION AND OBJECTIVE: Neuroendocrine prostate cancer (NEPC), arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy, is a lethal subtype of prostate cancer (PCa). Mechanisms contributing to NEPC development and its aggressiveness remain elusive. We previously reported that INSM1 is a novel sensitive marker for NEPC. We hypotheses that INSM1 involved in the NE transdifferentiation of prostate cancer. METHODS: Pan-neuroendocrine tumor database was reviewed. Patient-derived xenograft (PDX) models, clinical cohorts, cell lines and genetically engineered mouse models (Pbcre4 Rb1TP53) were utilized. RESULTS: Here, through pan-neuroendocrine tumor analyses, we identified INSM1 as a candidate master transcriptional regulator of poorly differentiated NEPC. Transcriptomic analyses of our patientderived xenograft (PDX) models, clinical cohorts, cell lines and genetically engineered mouse models (Pbcre4 Rb1TP53) confirmed INSM1 is significantly enriched in NEPC. INSM1 knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, ultimately leading to tumor growth arrest. This result was further confirmed in organoids derived from genetically engineered mouse tumor tissues. INSM1 ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells LNCAP subjected to androgen deprivation treatment. Mechanistically, INSM1 binded to the Hes1 promoter and represses Hes1. CONCLUSIONS: Collectively, these observations highlight the role of INSM1 in driving NEPC, and emphasize the potential therapeutic target for NEPC.