Sequential cancer mutations in cultured human intestinal stem cells

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 van de Wetering, Gerald Schwank, Meike Logtenberg, Edwin Cuppen, Hugo J. Snippert, Jan Paul Medema, Geert J. P. L. Kops and Hans Clevers ()
Additional contact information
Jarno Drost: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Richard H. van Jaarsveld: Cancer Genomics Netherlands, UMC Utrecht
Bas Ponsioen: Cancer Genomics Netherlands, UMC Utrecht
Cheryl Zimberlin: Cancer Genomics Netherlands, UMC Utrecht
Ruben van Boxtel: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Arjan Buijs: UMC Utrecht
Norman Sachs: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
René M. Overmeer: Cancer Genomics Netherlands, UMC Utrecht
G. Johan Offerhaus: UMC Utrecht
Harry Begthel: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Jeroen Korving: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Marc van de Wetering: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Gerald Schwank: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Meike Logtenberg: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Edwin Cuppen: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Hugo J. Snippert: Cancer Genomics Netherlands, UMC Utrecht
Jan Paul Medema: Cancer Genomics Netherlands, UMC Utrecht
Geert J. P. L. Kops: Cancer Genomics Netherlands, UMC Utrecht
Hans Clevers: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht

Nature, 2015, vol. 521, issue 7550, 43-47

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14415

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