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Visualization and targeting of LGR5+ human colon cancer stem cells

Author

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  • Mariko Shimokawa

    (Keio University School of Medicine)

  • Yuki Ohta

    (Keio University School of Medicine)

  • Shingo Nishikori

    (Keio University School of Medicine
    Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited)

  • Mami Matano

    (Keio University School of Medicine)

  • Ai Takano

    (Keio University School of Medicine)

  • Masayuki Fujii

    (Keio University School of Medicine)

  • Shoichi Date

    (Keio University School of Medicine
    Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Limited)

  • Shinya Sugimoto

    (Keio University School of Medicine)

  • Takanori Kanai

    (Keio University School of Medicine)

  • Toshiro Sato

    (Keio University School of Medicine)

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.

Suggested Citation

  • Mariko Shimokawa & Yuki Ohta & Shingo Nishikori & Mami Matano & Ai Takano & Masayuki Fujii & Shoichi Date & Shinya Sugimoto & Takanori Kanai & Toshiro Sato, 2017. "Visualization and targeting of LGR5+ human colon cancer stem cells," Nature, Nature, vol. 545(7653), pages 187-192, May.
    • Handle: RePEc:nat:nature:v:545:y:2017:i:7653:d:10.1038_nature22081
    DOI: 10.1038/nature22081
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    Citations

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    Cited by:

    1. Sandor Spisak & David Chen & Pornlada Likasitwatanakul & Paul Doan & Zhixin Li & Pratyusha Bala & Laura Vizkeleti & Viktoria Tisza & Pushpamali Silva & Marios Giannakis & Brian Wolpin & Jun Qi & Nilay, 2024. "Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Tsunaki Higa & Yasutaka Okita & Akinobu Matsumoto & Shogo Nakayama & Takeru Oka & Osamu Sugahara & Daisuke Koga & Shoichiro Takeishi & Hirokazu Nakatsumi & Naoki Hosen & Sylvie Robine & Makoto M. Take, 2022. "Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Sefora Conti & Valeria Venturini & Adrià Cañellas-Socias & Carme Cortina & Juan F. Abenza & Camille Stephan-Otto Attolini & Emily Middendorp Guerra & Catherine K. Xu & Jia Hui Li & Leone Rossetti & Gi, 2024. "Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Johannes Betge & Niklas Rindtorff & Jan Sauer & Benedikt Rauscher & Clara Dingert & Haristi Gaitantzi & Frank Herweck & Kauthar Srour-Mhanna & Thilo Miersch & Erica Valentini & Kim E. Boonekamp & Vero, 2022. "The drug-induced phenotypic landscape of colorectal cancer organoids," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Yi Liu & Efren Reyes & David Castillo-Azofeifa & Ophir D. Klein & Todd Nystul & Diane L. Barber, 2023. "Intracellular pH dynamics regulates intestinal stem cell lineage specification," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Adam E. Hall & Sebastian Öther-Gee Pohl & Patrizia Cammareri & Stuart Aitken & Nicholas T. Younger & Michela Raponi & Caroline V. Billard & Alfonso Bolado Carrancio & Aslihan Bastem & Paz Freile & Fio, 2022. "RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    7. Hengrui Liu, 2020. "A Prospective for the Potential Effect of Local Anesthetics on Stem-Like Cells in Colon Cancer," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 25(2), pages 18927-18930, January.

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