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Sequential cancer mutations in cultured human intestinal stem cells

Author

Listed:
  • Jarno Drost

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

  • Richard H. van Jaarsveld

    (Cancer Genomics Netherlands, UMC Utrecht
    Molecular Cancer Research, Centre for Molecular Medicine, UMC Utrecht)

  • Bas Ponsioen

    (Cancer Genomics Netherlands, UMC Utrecht
    Molecular Cancer Research, Centre for Molecular Medicine, UMC Utrecht)

  • Cheryl Zimberlin

    (Cancer Genomics Netherlands, UMC Utrecht
    Laboratory of Experimental Oncology and Radiobiology, Centre for Experimental Molecular Medicine, AMC)

  • Ruben van Boxtel

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

  • Arjan Buijs

    (UMC Utrecht)

  • Norman Sachs

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

  • René M. Overmeer

    (Cancer Genomics Netherlands, UMC Utrecht
    Molecular Cancer Research, Centre for Molecular Medicine, UMC Utrecht)

  • G. Johan Offerhaus

    (UMC Utrecht)

  • Harry Begthel

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

  • Jeroen Korving

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

  • Marc van de Wetering

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht
    Foundation Hubrecht Organoid Technology (HUB))

  • Gerald Schwank

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

  • Meike Logtenberg

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

  • Edwin Cuppen

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

  • Hugo J. Snippert

    (Cancer Genomics Netherlands, UMC Utrecht
    Molecular Cancer Research, Centre for Molecular Medicine, UMC Utrecht)

  • Jan Paul Medema

    (Cancer Genomics Netherlands, UMC Utrecht
    Laboratory of Experimental Oncology and Radiobiology, Centre for Experimental Molecular Medicine, AMC)

  • Geert J. P. L. Kops

    (Cancer Genomics Netherlands, UMC Utrecht
    Molecular Cancer Research, Centre for Molecular Medicine, UMC Utrecht)

  • Hans Clevers

    (Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Cancer Genomics Netherlands, UMC Utrecht)

Abstract

Crypt stem cells represent the cells of origin for intestinal neoplasia. Both mouse and human intestinal stem cells can be cultured in medium containing the stem-cell-niche factors WNT, R-spondin, epidermal growth factor (EGF) and noggin over long time periods as epithelial organoids that remain genetically and phenotypically stable. Here we utilize CRISPR/Cas9 technology for targeted gene modification of four of the most commonly mutated colorectal cancer genes (APC, P53 (also known as TP53), KRAS and SMAD4) in cultured human intestinal stem cells. Mutant organoids can be selected by removing individual growth factors from the culture medium. Quadruple mutants grow independently of all stem-cell-niche factors and tolerate the presence of the P53 stabilizer nutlin-3. Upon xenotransplantation into mice, quadruple mutants grow as tumours with features of invasive carcinoma. Finally, combined loss of APC and P53 is sufficient for the appearance of extensive aneuploidy, a hallmark of tumour progression.

Suggested Citation

  • Jarno Drost & Richard H. van Jaarsveld & Bas Ponsioen & Cheryl Zimberlin & Ruben van Boxtel & Arjan Buijs & Norman Sachs & René M. Overmeer & G. Johan Offerhaus & Harry Begthel & Jeroen Korving & Marc, 2015. "Sequential cancer mutations in cultured human intestinal stem cells," Nature, Nature, vol. 521(7550), pages 43-47, May.
    • Handle: RePEc:nat:nature:v:521:y:2015:i:7550:d:10.1038_nature14415
    DOI: 10.1038/nature14415
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    Cited by:

    1. Jina Yun & Simon Hansen & Otto Morris & David T. Madden & Clare Peters Libeu & Arjun J. Kumar & Cameron Wehrfritz & Aaron H. Nile & Yingnan Zhang & Lijuan Zhou & Yuxin Liang & Zora Modrusan & Michelle, 2023. "Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. 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.
    3. Lijing Yang & Lei Tu & Shilpa Bisht & Yiqing Mao & Daniel Petkovich & Sara-Jayne Thursby & Jinxiao Liang & Nibedita Patel & Ray-Whay Chiu Yen & Tina Largent & Cynthia Zahnow & Malcolm Brock & Kathy Ga, 2024. "Tissue-location-specific transcription programs drive tumor dependencies in colon cancer," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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