Key points are not available for this paper at this time.
Background: Second-generation hormonal therapy targeting androgen receptor signaling inhibits castration-resistant prostate cancer (CRPC), but the tumor eventually recurs as neuroendocrine prostate cancer (NEPC) and turns lethal. Objective: To differentiate and understand the mechanisms by which lineage plasticity contributes to the development of distinct NEPC subtypes from CRPC. Design, setting, and participants: We integrated single-cell RNA sequencing data from fresh human CRPC cases. This comprehensive approach allowed us to identify distinct NEPC subpopulations with high confidence. Outcome measurements and statistical analysis: We uncovered N-Myc and REST as key transcription factors promoting distinct neuroendocrine subtypes among 5,797 neuroendocrine-like epithelial cells using single-cell RNA sequencing and validated subset-specific progression using immunohistochemistry and multi-omics time course analysis of the publicly available transcriptomic dataset. Results and limitations: We identified three distinct neuroendocrine subtypes in CRPC: a REST-dependent subtype (NE I), an N-Myc-dependent subtype (NE II), and an N-Myc/REST subtype (NE I+II). We recapitulated N-Myc and REST subtypes in the mouse neuroendocrine cancer model dataset. Additionally, we identified STMN1 as a biomarker for the NE I+II subtype and validated its prognostic value in the TCGA dataset and 60 in-house CRPC tissues. Due to the advanced nature of CRPC, surgery is rarely performed, resulting in a small sample size. Therefore, validation of these signatures in larger CRPC cohorts is needed. Conclusions: Adeno-to-neuroendocrine lineage transition in prostate cancer leads to resistance to new hormone-targeted therapies. The lethal NEPC phenotype should be revealed earlier in the disease course of patients with CRPC, providing crucial clues for personalized precision medicine.
Hong et al. (Mon,) studied this question.