Pre-existing Castration-resistant Prostate Cancer-like Cells in Primary Prostate Cancer Promote Resistance to Hormonal Therapy.
Pre-existing Castration-resistant Prostate Cancer-like Cells in Primary Prostate Cancer Promote Resistance to Hormonal Therapy.
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原发性前列腺癌中预先存在的cast割前列腺癌样细胞可促进对激素疗法的抗性。
DOI：
10.1016/j.eururo.2021.12.039
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发表时间：
2022-05
期刊：
影响因子：
23.4
通讯作者：
Huang, Jiaoti
中科院分区：
文献类型：
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作者：
Cheng, Qing;Butler, William;Zhou, Yinglu;Zhang, Hong;Tang, Lu;Perkinson, Kathryn;Chen, Xufeng;Jiang, Xiaoyin ''Sara'';McCall, Shannon J.;Inman, Brant A.;Huang, Jiaoti
关键词：
针对雄激素受体的激素治疗可抑制前列腺癌（PCa），但肿瘤最终复发为去势抵抗性前列腺癌（CRPC）。了解早期PCa亚克隆发展为CRPC的机制。我们从新鲜的人前列腺癌病例中分离上皮细胞，包括原发性腺癌、局部复发性CRPC和转移性CRPC，并利用单细胞RNA测序来鉴定注定成为CRPC-腺癌或小细胞神经内分泌癌（SCNC）的亚群。我们利用单细胞RNA测序揭示了在23226个上皮细胞中促进疾病进展的动态转录重编程，并利用免疫组织化学和大量公开的基因组数据验证了亚群特异性进展。我们在hormone-naïve早期前列腺癌中发现了一小部分高可塑性的crpc样细胞，并证明其与生化复发和远处转移相关，独立于临床特征。我们发现，早期前列腺癌中已有的神经内分泌和crpc样细胞的亚型特异性谱系可塑性和克隆扩增引发了去势抗性的进展。crpc样细胞存在于前列腺癌发展的早期，并不完全是雄激素剥夺治疗过程中获得性进化选择的结果。致命的CRPC和SCNC表型应该在前列腺癌患者的病程中及早发现。在此，我们报道了原发性前列腺癌中存在预先存在的去势抵抗性前列腺癌（CRPC）样细胞，这代表了一种不同于雄激素剥夺治疗（ADT）后的适应机制的新型去势抵抗机制。肿瘤中已有神经内分泌和crpc样细胞增加的患者可能迅速对ADT产生耐药性，可能需要积极的早期干预。
Hormonal therapy targeting the androgen receptor inhibits prostate cancer (PCa), but the tumor eventually recurs as castration-resistant prostate cancer (CRPC). To understand the mechanisms by which subclones within early PCa develop into CRPC. We isolated epithelial cells from fresh human PCa cases, including primary adenocarcinoma, locally recurrent CRPC, and metastatic CRPC, and utilized single-cell RNA sequencing to identify subpopulations destined to become either CRPC-adeno or small cell neuroendocrine carcinoma (SCNC). We revealed dynamic transcriptional reprogramming that promotes disease progression among 23 226 epithelial cells using single-cell RNA sequencing, and validated subset-specific progression using immunohistochemistry and large cohorts of publically available genomic data. We identified a small fraction of highly plastic CRPC-like cells in hormone-naïve early PCa and demonstrated its correlation with biochemical recurrence and distant metastasis, independent of clinical characteristics. We show that progression toward castration resistance was initiated from subtype-specific lineage plasticity and clonal expansion of pre-existing neuroendocrine and CRPC-like cells in early PCa. CRPC-like cells are present early in the development of PCa and are not exclusively the result of acquired evolutionary selection during androgen deprivation therapy. The lethal CRPC and SCNC phenotypes should be targeted earlier in the disease course of patients with PCa. Here, we report the presence of pre-existing castration-resistant prostate cancer (CRPC)-like cells in primary prostate cancer, which represents a novel castration-resistant mechanism different from the adaptation mechanism after androgen deprivation therapy (ADT). Patients whose tumors harbor increased pre-existing neuroendocrine and CRPC-like cells may become rapidly resistant to ADT and may require aggressive early intervention.
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