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.
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Several preclinical human transformation organoid models have been developed through sequential CRISPR modifications of single or multiple oncogenic loci.
“Several preclinical human transformation organoid models have been developed through sequential CRISPR modifications of single or multiple oncogenic loci9–13.”
From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [13]
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- Authors
- Shimokawa, M., Ohta, Y., Nishikori, S., Matano, M., Takano, A., Fujii, M., Date, S., Sugimoto, S., Kanai, T., & Sato, T.
- Affiliations
- Keio University (JP)
- Otsuka (Japan) (JP)
- Corresponding author
- Sato, Toshiro
- Venue
- Nature
- Published
- 2017-03-29
- Volume
- 545
- Issue
- 7653
- Pages
- 187-192
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2599835027
- Cited by
- 728
- References
- 5
- Citations by year
- 2026: 47 · 2025: 60 · 2024: 79 · 2023: 66 · 2022: 102 · 2021: 100 · 2020: 93 · 2019: 69 · 2018: 78 · 2017: 34
- FWCI
- 33.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- China Scholarship Council
- Japan Society for the Promotion of Science (15K08974, 17K09395, 15J06065, 15K15297, 15J00981, 16J06433, 17J04827)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- Lgr5, colorectal cancer, cancer stem cells, tumor regrowth, cellular plasticity, lineage tracing, patient-derived organoids, CK20, self-renewal, tumor regression, anti-EGFR monoclonal antibody, combination chemotherapy, tumor heterogeneity
- MeSH terms
- Cell Self Renewal, Animals, Cell Differentiation, Colonic Neoplasms, Humans, Male, Organoids, Neoplastic Stem Cells, Cell Lineage, Xenograft Model Antitumor Assays, Receptors, G-Protein-Coupled, Cell Proliferation, Mice, Keratin-20, Gene Knock-In Techniques, Cell Tracking, Molecular Targeted Therapy
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