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

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

Author information

1
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. Electronic address: a.c.rios@prinsesmaximacentrum.nl.
2
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.
3
Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.
4
Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
5
3D Tissue Clearing and Lightsheet Microscopy Group, Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
6
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3050, Australia; The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC 3000, Australia.
7
TissuPATH, Melbourne, VIC 3149, Australia.
8
Centre for Dynamic Imaging, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
9
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC 3010, Australia.
10
Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Oncology, The Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia.
11
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. Electronic address: visvader@wehi.edu.au.

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.

KEYWORDS:

3D imaging; EMT; Elf5; breast cancer; cell-of-origin; clonal competition; lineage tracing; luminal progenitor; plasticity; tumor suppressor

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