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

Shimpei I Kubota; Kei Takahashi; Jun Nishida; Yasuyuki Morishita; Shogo Ehata; Kazuki Tainaka; Kohei Miyazono; Hiroki R Ueda

doi:10.1016/j.celrep.2017.06.010

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

Cell Rep. 2017 Jul 5;20(1):236-250. doi: 10.1016/j.celrep.2017.06.010.

Authors

Shimpei I Kubota¹, Kei Takahashi², Jun Nishida², Yasuyuki Morishita², Shogo Ehata², Kazuki Tainaka³, Kohei Miyazono⁴, Hiroki R Ueda⁵

Affiliations

¹ Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
² Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
³ Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Brain Research Institute, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata 951-8585, Japan.
⁴ Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: miyazono@m.u-tokyo.ac.jp.
⁵ Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 1-3 Yamadaoka, Suita, Osaka 565-5241, Japan. Electronic address: uedah-tky@umin.ac.jp.

PMID: 28683317
DOI: 10.1016/j.celrep.2017.06.010

Abstract

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.

Keywords: 3D cancer atlas; CUBIC-cancer analysis; cancer metastasis; epithelial-mesenchymal transition; pharmacotherapeutic profiling; tissue clearing; tumor microenvironment; whole-body profiling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
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*
Single-Cell Analysis / methods*
Tumor Microenvironment
Whole Body Imaging / methods*