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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134 Scopus citations


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 languageEnglish (US)
Article number7391
JournalNature communications
StatePublished - Jun 11 2015

Bibliographical note

Funding Information:
We thank the DKFZ Proteomics and Genomics Core Facility for next generation sequencing (Stephan Wolf and colleagues) and gene expression analysis (M. Bewerunge-Hudler and colleagues), DKFZ animal facility staff and in particular B. Goedecke-Weichert for support with animal work, B. Rumpel, L. Linke and D. Goldnik for technical support, D. Grimm for discussion, R. Wechsler-Reya and S. Brun for discussion and providing MERP tumours, K. Muguruma for Atoh1 antibody as well as K. Kawakami and Y. Takahashi for Tol2-related plasmids. This work has been supported by the Helmholtz Alliance ‘Preclinical Comprehensive Cancer Center’ (PCCC; Grant No. HA-305). C.B.K-.T. was supported by the Max Eder program of the German Cancer Aid (Deutsche Krebshilfe). B.T. was supported by a NIH training grant T32 AI 83196-5.

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