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

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 Largaespada; Martine F. Roussel; Andrey Korshunov; Guido Reifenberger; Stefan M. Pfister; Peter Lichter; Daisuke Kawauchi; Jan Gronych

doi:10.1038/ncomms8391

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

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 Largaespada, Martine F. Roussel, Andrey Korshunov, Guido Reifenberger, Stefan M. Pfister, Peter Lichter, Daisuke Kawauchi, Jan Gronych

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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.

Original language	English (US)
Article number	7391
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8391
State	Published - Jun 11 2015

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© 2015 Macmillan Publishers Limited. All rights reserved.

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Zuckermann, M., Hovestadt, V., Knobbe-Thomsen, C. B., Zapatka, M., Northcott, P. A., Schramm, K., Belic, J., Jones, D. T. W., Tschida, B., Moriarity, B., Largaespada, D., Roussel, M. F., Korshunov, A., Reifenberger, G., Pfister, S. M., Lichter, P., Kawauchi, D., & Gronych, J. (2015). Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling. Nature communications, 6, Article 7391. https://doi.org/10.1038/ncomms8391

Zuckermann, M, Hovestadt, V, Knobbe-Thomsen, CB, Zapatka, M, Northcott, PA, Schramm, K, Belic, J, Jones, DTW, Tschida, B, Moriarity, B , Largaespada, D, Roussel, MF, Korshunov, A, Reifenberger, G, Pfister, SM, Lichter, P, Kawauchi, D & Gronych, J 2015, 'Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling', Nature communications, vol. 6, 7391. https://doi.org/10.1038/ncomms8391

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

Abstract

Bibliographical note

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