The Affiliated XiangTan Central Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha 410082, Hunan Province, China.
Hunan Key Laboratory of Animal Models and Molecular Medicine, Hunan University, Changsha 410082, Hunan Province, China.
Sci Adv. 2024 Apr 5;10(14):eadm7098. doi: 10.1126/sciadv.adm7098. Epub 2024 Apr 3.
Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor (AR)-positive but neuroendocrine-null primary PCa subtype with morphologic and molecular characteristics of small cell carcinoma. Such small cell-like PCa (SCLPC) is clinically aggressive with low AR, but high stemness and proliferation, activity. Molecular characterization prioritizes protein translation, represented by up-regulation of many ribosomal protein genes, and SP1, a transcriptional factor that drives SCLPC phenotype and overexpresses in castration-resistant PCa (CRPC), as two potential therapeutic targets in AR-indifferent CRPC. An SP1-specific inhibitor, plicamycin, effectively suppresses CRPC growth in vivo. Homoharringtonine, a Food And Drug Administration-approved translation elongation inhibitor, impedes CRPC progression in preclinical models and patients with CRPC. We construct an SCLPC-specific signature capable of stratifying patients for drug selectivity. Our studies reveal the existence of SCLPC in admixed PCa pathology, which may mediate tumor relapse, and establish SP1 and translation elongation as actionable therapeutic targets for CRPC.
前列腺癌（PCa）的一个标志是组织病理学异质性。我们使用空间和并行的单细胞转录组学，报告了一种雄激素受体（AR）阳性但神经内分泌阴性的原发性 PCa 亚型，其具有小细胞癌的形态和分子特征。这种类似小细胞的 PCa（SCLPC）具有侵袭性，AR 水平低，但干性和增殖活性高。分子特征优先考虑蛋白质翻译，表现为许多核糖体蛋白基因上调，以及转录因子 SP1 上调，SP1 驱动 SCLPC 表型，并在去势抵抗性 PCa（CRPC）中过表达，这两个基因可能成为 AR 不依赖的 CRPC 的潜在治疗靶点。一种 SP1 特异性抑制剂 plicamycin 可有效抑制体内 CRPC 生长。已获美国食品和药物管理局批准的翻译延长抑制剂高三尖杉酯碱可阻碍临床前模型和 CRPC 患者的 CRPC 进展。我们构建了一个 SCLPC 特异性特征，可以对患者进行药物选择性分层。我们的研究揭示了 SCLPC 在混合 PCa 病理中的存在，这可能介导肿瘤复发，并确定 SP1 和翻译延长是 CRPC 的可行治疗靶点。
