Department of Urology, University of Washington, Seattle, Washington, USA.
Divison of Human Biology and.
J Clin Invest. 2019 Jul 30;129(10):4492-4505. doi: 10.1172/JCI128212.
Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with diverse drivers of disease progression and mechanisms of therapeutic resistance. We conducted deep phenotypic characterization of CRPC metastases and patient-derived xenograft (PDX) lines using whole genome RNA sequencing, gene set enrichment analysis and immunohistochemistry. Our analyses revealed five mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: (i) AR-high tumors (ARPC), (ii) AR-low tumors (ARLPC), (iii) amphicrine tumors composed of cells co-expressing AR and NE genes (AMPC), (iv) double-negative tumors (i.e. AR-/NE-; DNPC) and (v) tumors with small cell or NE gene expression without AR activity (SCNPC). RE1-silencing transcription factor (REST) activity, which suppresses NE gene expression, was lost in AMPC and SCNPC PDX models. However, knockdown of REST in cell lines revealed that attenuated REST activity drives the AMPC phenotype but is not sufficient for SCNPC conversion. We also identified a subtype of DNPC tumors with squamous differentiation and generated an encompassing 26-gene transcriptional signature that distinguished the five mCRPC phenotypes. Together, our data highlight the central role of AR and REST in classifying treatment-resistant mCRPC phenotypes. These molecular classifications could potentially guide future therapeutic studies and clinical trial design.
转移性去势抵抗性前列腺癌（mCRPC）是一种异质性疾病，其疾病进展的驱动因素和治疗耐药的机制多种多样。我们使用全基因组 RNA 测序、基因集富集分析和免疫组织化学对 CRPC 转移和患者来源的异种移植（PDX）系进行了深入的表型特征分析。我们的分析基于明确的雄激素受体（AR）或神经内分泌（NE）基因的表达，揭示了五种 mCRPC 表型：（i）AR 高肿瘤（ARPC），（ii）AR 低肿瘤（ARLPC），（iii）同时表达 AR 和 NE 基因的双相肿瘤（AMPC），（iv）双阴性肿瘤（即 AR-/NE-；DNPC）和（v）具有小细胞或 NE 基因表达而无 AR 活性的肿瘤（SCNPC）。抑制 NE 基因表达的 RE1 沉默转录因子（REST）活性在 AMPC 和 SCNPC PDX 模型中丢失。然而，细胞系中 REST 的敲低表明，减弱的 REST 活性驱动 AMPC 表型，但不足以导致 SCNPC 转化。我们还鉴定了具有鳞状分化的 DNPC 肿瘤的一个亚型，并生成了一个包含 26 个基因的转录特征，可区分五种 mCRPC 表型。总之，我们的数据强调了 AR 和 REST 在分类治疗抵抗性 mCRPC 表型中的核心作用。这些分子分类可能有助于指导未来的治疗研究和临床试验设计。
