Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells.
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.
['Goto|Norihiro|N|', 'Fukuda|Akihisa|A|', 'Yamaga|Yuichi|Y|', 'Yoshikawa|Takaaki|T|', 'Maruno|Takahisa|T|', 'Maekawa|Hisatsugu|H|', 'Inamoto|Susumu|S|', 'Kawada|Kenji|K|', 'Sakai|Yoshiharu|Y|', 'Miyoshi|Hiroyuki|H|0000-0001-7400-0714', 'Taketo|Makoto Mark|MM|', 'Chiba|Tsutomu|T|', 'Seno|Hiroshi|H|']
D000818:Animals D014408:Biomarkers, Tumor D064113:CRISPR-Cas Systems D063646:Carcinogenesis D002454:Cell Differentiation D019070:Cell Lineage D015179:Colorectal Neoplasms D000089742:Doublecortin-Like Kinases D055879:Gene Knock-In Techniques D006801:Humans D007413:Intestinal Mucosa D051379:Mice D008822:Mice, Transgenic D014411:Neoplastic Stem Cells D050810:Octamer Transcription Factors D061251:Primary Cell Culture D017346:Protein Serine-Threonine Kinases D034741:RNA, Small Interfering D053722:Receptors, Interleukin-17 D018874:Spheroids, Cellular D059008:Time-Lapse Imaging D014407:Tumor Cells, Cultured D015854:Up-Regulation D023041:Xenograft Model Antitumor Assays
Dclk1 IL17RB organoid CRISPR-Cas9