Abstract Purpose To elucidate tumor cell remodeling during androgen deprivation therapy (ADT) and disease progression in prostate cancer (PCa). Methods We performed an in-depth re-analysis of single-cell RNA sequencing data from 44 PCa samples derived from three prospective clinical trials. The meta-cohort comprised 13 localized ADT-naïve PCa samples, 25 hormone-sensitive prostate cancer (HSPC) samples obtained during androgen-deprivation therapy (ADT), and 6 metastatic castration-resistant prostate cancer (mCRPC) samples. Malignant and benign epithelial cells were distinguished using inferCNVpy, and tumor cell–intrinsic transcriptional programs were compared across disease stages. Results Compared with localized PCa, tumor cells from HSPC samples exhibited marked suppression of androgen response pathways and enrichment of apoptosis-related programs. Notably, ADT induced activation of immune-associated transcriptional programs within tumor cells, including interferon-α/γ responses and antigen processing and presentation pathways. In contrast, tumor cells from mCRPC samples displayed enrichment of MYC signaling, suggesting a potential role for MYC as a driver of castration resistance. In addition, FOLH1 expression was significantly upregulated in mCRPC tumor cells. Conclusion This study provides a comprehensive single-cell transcriptional landscape of PCa progression from ADT-naïve disease to mCRPC and highlights the activation of immune response during ADT therapy and the role of MYC-driven programs in castration-resistant disease.
Wei et al. (Thu,) studied this question.
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