PO.TB09.02 · 肿瘤生物学
Rb1缺失定义了转移性前列腺癌亚型中不同的迁移历史
Rb1 loss defines distinct migration histories in metastatic prostate cancer subtypes
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
Rb1缺失是致死性去势抵抗性前列腺癌(CRPC)的标志性特征，但其在塑造转移播散模式中的作用仍知之甚少。我们利用EvoCaP体细胞工程小鼠模型(SEMM)，构建了Pten/Trp53/Rb1缺陷型(2PR)小鼠，并将其与Pten/Trp53缺陷型(2P)对照进行比较。Rb1缺失显著增加了转移负荷，尤其是向内脏器官的转移，并促进了神经内分泌(NE)分化。谱系追踪显示，2PR肿瘤建立了转移枢纽器官，从而向多个继发部位播散级联转移。组织学上，2PR肿瘤表现出明显的NE和间充质样(ML)区室，其中NE区域显示beta-catenin和EZH2表达升高，这些是侵袭性去势抵抗性前列腺癌的标志物，包括：CRPC-WNT(Wnt信号驱动)和CRPC-NE(EZH2高表达)亚型。源自2PR肿瘤的类器官证实了这些转录变化，并显示出对EZH2和WNT抑制剂增强的敏感性。这些发现揭示了Rb1缺失如何驱动前列腺癌的谱系可塑性和转移演进，并确定了这一致死性疾病亚型中的治疗脆弱性。
查看英文原文 English abstract
Rb1 loss is a hallmark of lethal castration-resistant prostate cancer (CRPC), yet its role in shaping metastatic dissemination patterns remains poorly understood. Using our EvoCaP somatically engineered mouse model (SEMM), we generated Pten / Trp53 / Rb1 -deficient ( 2PR ) mice and compared them to Pten / Trp53 -deficient ( 2P ) controls. Loss of Rb1 dramatically increased metastatic burden, particularly to visceral organs, and promoted neuroendocrine (NE) differentiation. Lineage tracing revealed that 2PR tumors establish metastatic hub organs that seed cascade dissemination to multiple secondary sites. Histologically, 2PR tumors displayed distinct NE and mesenchymal-like (ML) compartments, with NE regions showing elevated beta-catenin and EZH2 expression, markers of aggressive castration-resistant prostate cancers including: CRPC-WNT (Wnt signaling driven) and CRPC-NE (EZH2-high) subtypes. Organoids derived from 2PR tumors confirmed these transcriptional changes and showed enhanced sensitivity to EZH2 and WNT inhibitors. These findings reveal how Rb1 loss drives lineage plasticity and metastatic evolution in prostate cancer, identifying therapeutic vulnerabilities in this lethal disease subtype.
利益披露 Disclosure
D. G. Nowak,
University of Bristol/Exonate I received an Exonate royalty share..
Arvinas Inc. I used to own stock in Arvinas..
R. N. Serio, None..
L. M. Brault, None..
D. V. Gargiulo, None..
R. Hassett, None..
R. J. Chaffee, None..
S. J. Staklinski, None..
B. Lu, None..
A. C. Siepel, None.