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Somatic genome editing with the RCAS/TVA-CRISPR/Cas9 system for precision tumor modeling

Barbara Oldrini, Álvaro Curiel-García, Carolina Marques, Veronica Matia, Özge Uluçkan, Raul Torres-Ruiz, Sandra Rodriguez-Perales, Jason T. Huse, Massimo Squatrito
doi: https://doi.org/10.1101/162669
Barbara Oldrini
1Seve Ballesteros Foundation Brain Tumor Group, Cancer Cell Biology Program, Spanish National Cancer Research Center, CNIO, 28029 Madrid, Spain.
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Álvaro Curiel-García
1Seve Ballesteros Foundation Brain Tumor Group, Cancer Cell Biology Program, Spanish National Cancer Research Center, CNIO, 28029 Madrid, Spain.
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Carolina Marques
1Seve Ballesteros Foundation Brain Tumor Group, Cancer Cell Biology Program, Spanish National Cancer Research Center, CNIO, 28029 Madrid, Spain.
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Veronica Matia
1Seve Ballesteros Foundation Brain Tumor Group, Cancer Cell Biology Program, Spanish National Cancer Research Center, CNIO, 28029 Madrid, Spain.
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Özge Uluçkan
2Genes, Development, and Disease Group, Cancer Cell Biology Program, Spanish National Cancer Research Centre, CNIO, 28029 Madrid, Spain.
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Raul Torres-Ruiz
3Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Center, CNIO, 28029 Madrid, Spain.
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Sandra Rodriguez-Perales
3Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Center, CNIO, 28029 Madrid, Spain.
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Jason T. Huse
4Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Massimo Squatrito
1Seve Ballesteros Foundation Brain Tumor Group, Cancer Cell Biology Program, Spanish National Cancer Research Center, CNIO, 28029 Madrid, Spain.
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  • For correspondence: msquatrito@cnio.es
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Abstract

It has been gradually established that the vast majority of human tumors are extraordinarily heterogeneous at a genetic level. To accurately recapitulate this complexity, it is now evident that in vivo animal models of cancers will require to recreate not just a handful of simple genetic alterations, but possibly dozens and increasingly intricate. Here, we have combined 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 (NSCs) of a variety of known tumor suppressor genes (Trp53, Cdkn2a and Pten), in combination with the expression of an oncogene driver, leads to high-grade glioma formation. Moreover, by simultaneous delivery of pairs of guide RNAs (gRNAs) we generated different gene fusions, either by chromosomal deletion (Bcan-Ntrk1) or by chromosomal translocation (Myb-Qk), and we show that they have transforming potential in vitro and in vivo. Lastly, using homology-directed-repair (HDR), we also produced tumors carrying the Braf V600E mutation, frequently identified in a variety of subtypes of gliomas. In summary, we have developed an extremely powerful and 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.

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Posted August 14, 2017.
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Somatic genome editing with the RCAS/TVA-CRISPR/Cas9 system for precision tumor modeling
Barbara Oldrini, Álvaro Curiel-García, Carolina Marques, Veronica Matia, Özge Uluçkan, Raul Torres-Ruiz, Sandra Rodriguez-Perales, Jason T. Huse, Massimo Squatrito
bioRxiv 162669; doi: https://doi.org/10.1101/162669
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Somatic genome editing with the RCAS/TVA-CRISPR/Cas9 system for precision tumor modeling
Barbara Oldrini, Álvaro Curiel-García, Carolina Marques, Veronica Matia, Özge Uluçkan, Raul Torres-Ruiz, Sandra Rodriguez-Perales, Jason T. Huse, Massimo Squatrito
bioRxiv 162669; doi: https://doi.org/10.1101/162669

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