Somatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Barbara Oldrini, Álvaro Curiel-García, Carolina Marques, Veronica Matia, Özge Uluçkan, Osvaldo Graña-Castro, Raul Torres-Ruiz, Sandra Rodriguez-Perales, Jason T. Huse, Massimo Squatrito

ABSTRACT

To accurately recapitulate the heterogeneity of human diseases, animal models require to recreate multiple complex genetic alterations. Here, we combine the RCAS-TVA system with the CRISPR-Cas9 genome editing tools for precise modeling of human tumors. We show that somatic deletion in neural stem cells of a variety of known tumor suppressor genes (Trp53, Cdkn2a, and Pten) leads to high-grade glioma formation. Moreover, by simultaneous delivery of pairs of guide RNAs we generate different gene fusions with oncogenic potential, either by chromosomal deletion (Bcan-Ntrk1) or by chromosomal translocation (Myb-Qk). Lastly, using homology-directed-repair, we also produce tumors carrying the homologous mutation to human BRAF V600E, frequently identified in a variety of tumors, including different types of gliomas. In summary, we have developed an extremely versatile mouse model for in vivo somatic genome editing, that will elicit the generation of more accurate cancer models particularly appropriate for pre-clinical testing. More... »

PAGES

1466

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41467-018-03731-w

DOI

http://dx.doi.org/10.1038/s41467-018-03731-w

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1103149618

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29654229


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468 schema:name Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA
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470 https://www.grid.ac/institutes/grid.7719.8 schema:alternateName Spanish National Cancer Research Centre
471 schema:name Bioinformatics Unit, Structural Biology and Biocomputing Programme, CNIO, 28029, Madrid, Spain
472 Genes, Development, and Disease Group, Cancer Cell Biology Program, Spanish National Cancer Research Centre, CNIO, 28029, Madrid, Spain
473 Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Center, CNIO, 28029, Madrid, Spain
474 Seve Ballesteros Foundation Brain Tumor Group, Cancer Cell Biology Program, Spanish National Cancer Research Center, CNIO, 28029, Madrid, Spain
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