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

Authors:

• Rios, Anne C.
• Capaldo, Bianca D.
• Vaillant, François
• Pal, Bhupinder
• van Ineveld, Ravian
• Dawson, Caleb A.
• Chen, Yunshun
• Nolan, Emma
• Fu, Nai Yang
• Jackling, Felicity C.
• Devi, Sapna
• Clouston, David
• Whitehead, Lachlan
• Smyth, Gordon K.
• Mueller, Scott N.
• Lindeman, Geoffrey J.
• Visvader, Jane E.

Details:

Cancer Cell, Volume 35, Issue 4, 2019-04-15

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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 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.