Rapid modelling of cooperating genetic events in cancer through somatic genome editing
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Author(s)
Papagiannakopoulos, Thales
Romero, Rodrigo
Tammela, Tuomas
Bauer, Matthew R.
Subbaraj, Lakshmipriya
Bronson, Roderick T.
Xue, Wen
Sanchez-Rivera, Francisco Jav
Joshi, Nik
Bhutkar, Arjun
Date Issued
October 2014
Journal
Nature
Publisher
Nature Publishing Group
Citation
Sánchez-Rivera, Francisco J., Thales Papagiannakopoulos, Rodrigo Romero, Tuomas Tammela, Matthew R. Bauer, Arjun Bhutkar, Nikhil S. Joshi, et al. “Rapid Modelling of Cooperating Genetic Events in Cancer through Somatic Genome Editing.” Nature 516, no. 7531 (October 22, 2014): 428–431.
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Author's final manuscript
Abstract
Cancer is a multistep process that involves mutations and other alterations in oncogenes and tumour suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Here we describe a novel CRISPR/Cas9-based approach for rapid functional investigation of candidate genes in well-established autochthonous mouse models of cancer. Using a Kras[superscript G12D]-driven lung cancer model, we performed functional characterization of a panel of tumour suppressor genes with known loss-of-function alterations in human lung cancer. Cre-dependent somatic activation of oncogenic Kras[superscript G12D] combined with CRISPR/Cas9-mediated genome editing of tumour suppressor genes resulted in lung adenocarcinomas with distinct histopathological and molecular features. This rapid somatic genome engineering approach enables functional characterization of putative cancer genes in the lung and other tissues using autochthonous mouse models. We anticipate that this approach can be used to systematically dissect the complex catalogue of mutations identified in cancer genome sequencing studies.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/nature13906
