title: Rapid modelling of cooperating genetic events in cancer through somatic genome editing.
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(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(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.
authors.affiliation: 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Sánchez-Rivera
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Thales
authors.initials: T
authors.lastname: Papagiannakopoulos
authors.affiliation: 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Romero
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Bauer
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Bhutkar
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Nikhil S
authors.initials: NS
authors.lastname: Joshi
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Lakshmipriya
authors.initials: L
authors.lastname: Subbaraj
authors.affiliation: 1] Tufts University, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xue
authors.affiliation: 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D064130:CRISPR-Associated Proteins; D064113:CRISPR-Cas Systems; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D004195:Disease Models, Animal; D000072669:Gene Editing / Q000379:methods*; D016147:Genes, Tumor Suppressor; D016678:Genome; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics
chemical_list: D064130:CRISPR-Associated Proteins