Tumor-Associated Macrophage Exosomal miR-142-5p Drives Prostate Cancer Neuroendocrine Differentiation via RERG/Ras/ERK Axis.

Androgen deprivation therapy (ADT) for prostate cancer (PCa) leads to lineage plasticity in PCa cells, promoting the emergence of androgen receptor-negative neuroendocrine prostate cancer (NEPC). NEPC is a highly aggressive subtype with poor prognosis and limited treatment options. Tumor-associated macrophages (TAMs) contribute to tumor progression through exosome-mediated communication. In our previous study, we analyzed RNA-seq data to identify key genes involved in PCa progression, and the RERG gene emerged as a significant candidate that suppresses neuroendocrine differentiation (NED). In this study, we demonstrate that RERG expression is significantly reduced in CRPC cells and NEPC tissues, and its downregulation activates the Ras/ERK signaling pathway, which plays a crucial role in promoting NED. Additionally, miR-142-5p, transferred from TAMs via exosomes, downregulates RERG expression and activates the Ras/ERK pathway, thereby promoting PCa progression and NED. In vitro, miR-142-5p enhanced PCa cell proliferation, migration, invasion, and NED, while RERG overexpression reversed these effects. In vivo, RERG knockdown significantly promoted tumor growth and NED in a xenograft model. These findings highlight the role of TAM-derived miR-142-5p in regulating NED and suggest that targeting the RERG/Ras/ERK axis may provide a novel therapeutic approach for NEPC.