Journal
CANCER CELL
Volume 35, Issue 4, Pages 618-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.02.010
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Funding
- Australian National Health and Medical Research Council (NHMRC) [461221, 1016701, 1024852, 1054618]
- NHMRC IRIISS
- Victorian State Government through VCA funding and Operational Infrastructure Support
- Australian Cancer Research Foundation
- National Breast Cancer Foundation (NBCF)/Cure Cancer Australia Fellowship
- NHMRC Fellowships [1042629, 490037, 637307]
- NHMRC [1037230, 1102742]
- National Health and Medical Research Council of Australia [1102742] Funding Source: NHMRC
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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 lumina! 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.
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