Lineage tracing and targeting of IL17RB⁺ tuft cell-like human colorectal cancer stem cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-06, Vol.116 (26), p.12996-13005
• Main Authors: Goto, Norihiro, Fukuda, Akihisa, Yamaga, Yuichi, Yoshikawa, Takaaki, Maruno, Takahisa, Maekawa, Hisatsugu, Inamoto, Susumu, Kawada, Kenji, Sakai, Yoshiharu, Miyoshi, Hiroyuki, Taketo, Makoto Mark, Chiba, Tsutomu, Seno, Hiroshi
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Biological Sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer; Carcinogenesis; Cell Differentiation; Cell Lineage; Cell surface; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; CRISPR; CRISPR-Cas Systems - genetics; Differentiation (biology); Gene Knock-In Techniques; Humans; Interleukin 1; Interleukin 13; Intestinal Mucosa - cytology; Intestinal Mucosa - pathology; Intestine; Mice; Mice, Transgenic; Neoplastic Stem Cells - pathology; Octamer Transcription Factors - metabolism; Organoids; PNAS Plus; Primary Cell Culture; Protein-Serine-Threonine Kinases - genetics; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - metabolism; RNA, Small Interfering - metabolism; Spheroids, Cellular; Stem cell transplantation; Stem cells; Surface markers; Target recognition; Therapeutic applications; Time-Lapse Imaging; Tumor cells; Tumor Cells, Cultured; Tumors; Up-Regulation; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1900251116

Cancer stem cell (CSC)-specific markers may be potential therapeutic targets. We previously identified that Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal adenomas. Based on the analysis of mouse Dclk1⁺ tumor cells, we aimed to identify a CSC-specific cell surface marker in human colorectal cancers (hCRCs) and validate the therapeutic effect of targeting it. IL17RB was distinctively expressed by Dclk1⁺ mouse intestinal tumor cells. Using Il17rb-CreERT2-IRES-EGFP mice, we show that IL17RB marked intestinal TSCs in an IL13-dependent manner. Tuft cell-like cancer cells were detected in a subset of hCRCs. In these hCRCs, lineage-tracing experiments in CRISPR-Cas9–mediated IL17RB-CreERT2 knockin organoids and xenograft tumors revealed that IL17RB marks CSCs that expand independently of IL-13. We observed up-regulation of POU2F3, a master regulator of tuft cell differentiation, and autonomous tuft cell-like cancer cell differentiation in the hCRCs. Furthermore, long-term ablation of IL17RB-expressing CSCs strongly suppressed the tumor growth in vivo. These findings reveal insights into a CSC-specific marker IL17RB in a subset of hCRCs, and preclinically validate IL17RB⁺ CSCs as a cancer therapeutic target.