Whole-Body Profiling of Cancer Metastasis with Single-Cell Resolution

• Published in: Cell reports (Cambridge) Vol. 20; no. 1; pp. 236 - 250
• Main Authors: Kubota, Shimpei I., Takahashi, Kei, Nishida, Jun, Morishita, Yasuyuki, Ehata, Shogo, Tainaka, Kazuki, Miyazono, Kohei, Ueda, Hiroki R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.07.2017; Elsevier
• Subjects: 3D cancer atlas; Animals; cancer metastasis; Cell Line, Tumor; CUBIC-cancer analysis; Epithelial-Mesenchymal Transition; Female; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental - diagnostic imaging; Neoplasms, Experimental - pathology; Optical Imaging - methods; pharmacotherapeutic profiling; Single-Cell Analysis - methods; tissue clearing; Tumor Microenvironment; Whole Body Imaging - methods; whole-body profiling; tissue clearing; epithelial-mesenchymal transition; tumor microenvironment; 3D cancer atlas; pharmacotherapeutic profiling; CUBIC-cancer analysis; whole-body profiling; cancer metastasis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.06.010

Stochastic and proliferative events initiated from a single cell can disrupt homeostatic balance and lead to fatal disease processes such as cancer metastasis. To overcome metastasis, it is necessary to detect and quantify sparsely distributed metastatic cells throughout the body at early stages. Here, we demonstrate that clear, unobstructed brain/body imaging cocktails and computational analysis (CUBIC)-based cancer (CUBIC-cancer) analysis with a refractive index (RI)-optimized protocol enables comprehensive cancer cell profiling of the whole body and organs. We applied CUBIC-cancer analysis to 13 mouse models using nine cancer cell lines and spatiotemporal quantification of metastatic cancer progression at single-cell resolution. CUBIC-cancer analysis suggests that the epithelial-mesenchymal transition promotes not only extravasation but also cell survival at metastatic sites. CUBIC-cancer analysis is also applicable to pharmacotherapeutic profiling of anti-tumor drugs. CUBIC-cancer analysis is compatible with in vivo bioluminescence imaging and 2D histology. We suggest that a scalable analytical pipeline with these three modalities may contribute to addressing currently incurable metastatic diseases. [Display omitted] •RI-optimized CUBIC protocol enables whole-body examination of cancer models•CUBIC is applicable to analysis of micrometastases at single-cell resolution•CUBIC analysis bridges the resolution gap between in vivo imaging and histology•CUBIC-cancer analysis is useful for profiling biological processes in whole organs Kubota et al. find that CUBIC-cancer analysis can profile cancer metastasis at a single-cell level in a whole-animal context. In addition, CUBIC-cancer analysis can bridge the resolution gap between in vivo bioluminescence imaging and histology. This analytical pipeline would contribute to the profiling of biological functions of whole organs.