title: Visualization and targeting of LGR5+human colon cancer stem cells.
abstract: The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xenotransplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain unclear. Here, we show that human LGR5+colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a tamoxifen-inducible Cre knock-in allele of LGR5 reveal the self-renewal and differentiation capacity of LGR5+tumour cells. Selective ablation of LGR5+CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+CSCs. KRT20 knock-in reporter marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+CSCs and contributing to tumour regrowth after LGR5+CSC ablation. We also show that combined chemotherapy potentiates targeting of LGR5+CSCs. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Shimokawa
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.|Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited, Shiga, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishikori
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Matano
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Takano
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.|Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited, Shiga, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Date
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Sugimoto
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.affiliation: Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D058948:Cell Tracking; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055879:Gene Knock-In Techniques; D006801:Humans; D053554:Keratin-20 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D009940:Organoids / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C507499:KRT20 protein, human; D053554:Keratin-20; C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled