通过大规模单细胞分辨率 3D 成像揭示乳腺肿瘤中的克隆内可塑性。

Intraclonal Plasticity in Mammary Tumors Revealed through Large-Scale Single-Cell Resolution 3D Imaging.

机构信息

Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.

出版信息

Cancer Cell. 2019 Apr 15;35(4):618-632.e6. doi: 10.1016/j.ccell.2019.02.010. Epub 2019 Mar 28.

DOI:10.1016/j.ccell.2019.02.010

PMID:30930118

Abstract

Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression. Expression profiling of clones arising in Pten/Trp53-deficient tumors identified distinct molecular signatures. Strikingly, most clones harbored cells that had undergone an epithelial-to-mesenchymal transition, indicating widespread, inherent plasticity. Hence, an integrative pipeline that combines lineage tracing, 3D imaging, and clonal RNA sequencing technologies offers a comprehensive path for studying mechanisms underlying heterogeneity in whole tumors.

摘要

乳腺肿瘤本质上是异质性的，但肿瘤进展过程中不断变化的细胞组织尚不清楚。在这里，我们报告了一种基于一步清除剂的快速、大规模单细胞分辨率 3D 成像方案，该方案能够以单细胞分辨率可视化正常组织结构和整个肿瘤。对靶向基底或腔前体细胞的乳腺癌多色谱系追踪模型的成像显示，在进展过程中存在明显的克隆限制。对 Pten/Trp53 缺失肿瘤中出现的克隆进行表达谱分析，确定了不同的分子特征。引人注目的是，大多数克隆都含有经历上皮间质转化的细胞，表明广泛存在内在的可塑性。因此，整合谱系追踪、3D 成像和克隆 RNA 测序技术的综合管道为研究整个肿瘤异质性的机制提供了一种全面的途径。