Single-Cell Analysis Identifies LY6D as a Marker Linking Castration-Resistant Prostate Luminal Cells to Prostate Progenitors and Cancer
Single-Cell Analysis Identifies LY6D as a Marker Linking Castration-Resistant Prostate Luminal Cells to Prostate Progenitors and Cancer
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DOI：
10.1016/j.celrep.2018.11.069
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发表时间：
2018-12-18
期刊：
影响因子：
8.8
通讯作者：
Baena, Esther
中科院分区：
文献类型：
--
作者：
Barros-Silva, Joao D.;Linn, Douglas E.;Baena, Esther
去势抵抗（CR）细胞的确切身份及其与CR前列腺癌（CRPC）的关系尚未得到解决。我们使用单细胞基因分析来分析基底和腔室的分子异质性。在腔室，我们确定了一个子集的细胞本质上耐去势与双谱系基因表达模式。我们发现LY 6D是具有多能分化和丰富的类器官形成能力的CR前列腺祖细胞的标志物。谱系追踪进一步揭示了LY 6D（+）CR管腔细胞可以产生LY 6D（-）管腔细胞。相反，在缺乏PTEN的管腔细胞中，LY 6D（+）细胞主要产生LY 6D（+）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，LY 6D表达与早期疾病进展相关，包括进展为CRPC。因此，我们的研究确定了一个亚群的管腔祖细胞的特征是LY 6D表达和内在的去势抵抗。LY 6D可作为晚期前列腺癌的预后指标。
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.