Proceedings of the National Academy of Sciences - PNAS, 2019-06, Vol.116 (26), p.12996-13005
2019
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- Autor(en) / Beteiligte
- Titel
- Lineage tracing and targeting of IL17RB⁺ tuft cell-like human colorectal cancer stem cells
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2019-06, Vol.116 (26), p.12996-13005
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1900251116Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6601016
- Format
- –
- Schlagworte
- 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