| Title | Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells. |
| Publication Type | Journal Article |
| Year of Publication | 2019 |
| Authors | Goto N, Fukuda A, Yamaga Y, Yoshikawa T, Maruno T, Maekawa H, Inamoto S, Kawada K, Sakai Y, Miyoshi H, Taketo MMark, Chiba T, Seno H |
| Journal | Proc Natl Acad Sci U S A |
| Volume | 116 |
| Issue | 26 |
| Pagination | 12996-13005 |
| Date Published | 2019 Jun 25 |
| ISSN | 1091-6490 |
| Keywords | Animals, Biomarkers, Tumor, Carcinogenesis, Cell Differentiation, Cell Lineage, Colorectal Neoplasms, CRISPR-Cas Systems, Doublecortin-Like Kinases, Gene Knock-In Techniques, Humans, Intestinal Mucosa, Mice, Mice, Transgenic, Neoplastic Stem Cells, Octamer Transcription Factors, Primary Cell Culture, Protein Serine-Threonine Kinases, Receptors, Interleukin-17, RNA, Small Interfering, Spheroids, Cellular, Time-Lapse Imaging, Tumor Cells, Cultured, Up-Regulation, Xenograft Model Antitumor Assays |
| Abstract | 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. |
| DOI | 10.1073/pnas.1900251116 |
| Alternate Journal | Proc Natl Acad Sci U S A |
| PubMed ID | 31182574 |
| PubMed Central ID | PMC6601016 |