Prostate Oncobiology, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, UK; Belfast-Manchester Movember Centre of Excellence, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park SK10 4TG, UK.
Division of Genetics, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Cell Rep. 2018 Dec 18;25(12):3504-3518.e6. doi: 10.1016/j.celrep.2018.11.069.
The exact identity of castrate-resistant (CR) cells and their relation to CR prostate cancer (CRPC) is unresolved. We use single-cell gene profiling to analyze the molecular heterogeneity in basal and luminal compartments. Within the luminal compartment, we identify a subset of cells intrinsically resistant to castration with a bi-lineage gene expression pattern. We discover LY6D as a marker of CR prostate progenitors with multipotent differentiation and enriched organoid-forming capacity. Lineage tracing further reveals that LY6D CR luminal cells can produce LY6D luminal cells. In contrast, in luminal cells lacking PTEN, LY6D cells predominantly give rise to LY6D tumor cells, contributing to high-grade PIN lesions. Gene expression analyses in patients' biopsies indicate that LY6D expression correlates with early disease progression, including progression to CRPC. Our studies thus identify a subpopulation of luminal progenitors characterized by LY6D expression and intrinsic castration resistance. LY6D may serve as a prognostic maker for advanced prostate cancer.
确切的去势抵抗（CR）细胞及其与 CR 前列腺癌（CRPC）的关系仍未解决。我们使用单细胞基因谱分析来分析基底和管腔隔室中的分子异质性。在管腔隔室中，我们确定了一组固有对去势具有抗性的细胞，具有双谱系基因表达模式。我们发现 LY6D 是具有多能分化和丰富类器官形成能力的 CR 前列腺祖细胞的标志物。谱系追踪进一步表明，LY6D CR 管腔细胞可以产生 LY6D 管腔细胞。相比之下，在缺乏 PTEN 的管腔细胞中，LY6D 细胞主要产生 LY6D 肿瘤细胞，导致高级别 PIN 病变。患者活检中的基因表达分析表明，LY6D 表达与疾病早期进展相关，包括进展为 CRPC。因此，我们的研究确定了一个以 LY6D 表达和内在去势抵抗为特征的管腔祖细胞亚群。LY6D 可能可作为晚期前列腺癌的预后标志物。
