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Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling

Author

Listed:
  • Marc Zuckermann

    (German Cancer Research Center (DKFZ))

  • Volker Hovestadt

    (German Cancer Research Center (DKFZ))

  • Christiane B. Knobbe-Thomsen

    (Heinrich Heine University Düsseldorf
    German Cancer Consortium (DKTK), partner site Essen/Düsseldorf)

  • Marc Zapatka

    (German Cancer Research Center (DKFZ))

  • Paul A. Northcott

    (German Cancer Research Center (DKFZ))

  • Kathrin Schramm

    (German Cancer Research Center (DKFZ))

  • Jelena Belic

    (German Cancer Research Center (DKFZ))

  • David T. W. Jones

    (German Cancer Research Center (DKFZ))

  • Barbara Tschida

    (Masonic Cancer Center, University of Minnesota)

  • Branden Moriarity

    (Masonic Cancer Center, University of Minnesota)

  • David Largaespada

    (Masonic Cancer Center, University of Minnesota)

  • Martine F. Roussel

    (Tumor Cell Biology, St Jude Children’s Research Hospital)

  • Andrey Korshunov

    (University of Heidelberg
    Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ))

  • Guido Reifenberger

    (Heinrich Heine University Düsseldorf
    German Cancer Consortium (DKTK), partner site Essen/Düsseldorf)

  • Stefan M. Pfister

    (German Cancer Research Center (DKFZ))

  • Peter Lichter

    (German Cancer Research Center (DKFZ))

  • Daisuke Kawauchi

    (German Cancer Research Center (DKFZ))

  • Jan Gronych

    (German Cancer Research Center (DKFZ))

Abstract

In vivo functional investigation of oncogenes using somatic gene transfer has been successfully exploited to validate their role in tumorigenesis. For tumour suppressor genes this has proven more challenging due to technical aspects. To provide a flexible and effective method for investigating somatic loss-of-function alterations and their influence on tumorigenesis, we have established CRISPR/Cas9-mediated somatic gene disruption, allowing for in vivo targeting of TSGs. Here we demonstrate the utility of this approach by deleting single (Ptch1) or multiple genes (Trp53, Pten, Nf1) in the mouse brain, resulting in the development of medulloblastoma and glioblastoma, respectively. Using whole-genome sequencing (WGS) we characterized the medulloblastoma-driving Ptch1 deletions in detail and show that no off-targets were detected in these tumours. This method provides a fast and convenient system for validating the emerging wealth of novel candidate tumour suppressor genes and the generation of faithful animal models of human cancer.

Suggested Citation

  • Marc Zuckermann & Volker Hovestadt & Christiane B. Knobbe-Thomsen & Marc Zapatka & Paul A. Northcott & Kathrin Schramm & Jelena Belic & David T. W. Jones & Barbara Tschida & Branden Moriarity & David , 2015. "Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8391
    DOI: 10.1038/ncomms8391
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    Cited by:

    1. Huiqiang Cai & Bin Zhang & Johanne Ahrenfeldt & Justin V. Joseph & Maria Riedel & Zongliang Gao & Sofie K. Thomsen & Ditte S. Christensen & Rasmus O. Bak & Henrik Hager & Mikkel H. Vendelbo & Xin Gao , 2024. "CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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