Rapid modelling of cooperating genetic events in cancer through somatic genome editing
Author(s)Papagiannakopoulos, Thales; Romero, Rodrigo; Tammela, Tuomas; Bauer, Matthew R.; Subbaraj, Lakshmipriya; Bronson, Roderick T.; Xue, Wen; Sanchez-Rivera, Francisco Jav; Bhutkar, Arjun (AJ); Joshi, Nik; Jacks, Tyler E.; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Nature Publishing Group
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.
Author's final manuscript