title: Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells.
abstract: Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM-ESCs by Flp recombinase-mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM-ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof-of-principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer.
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ivo J
authors.initials: IJ
authors.lastname: Huijbers
authors.forename: Rahmen
authors.initials: R
authors.lastname: Bin Ali
authors.forename: Colin
authors.initials: C
authors.lastname: Pritchard
authors.forename: Miranda
authors.initials: M
authors.lastname: Cozijnsen
authors.forename: Min-Chul
authors.initials: MC
authors.lastname: Kwon
authors.forename: Natalie
authors.initials: N
authors.lastname: Proost
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: Hilda
authors.initials: H
authors.lastname: de Vries
authors.forename: Jitendra
authors.initials: J
authors.lastname: Badhai
authors.forename: Kate
authors.initials: K
authors.lastname: Sutherland
authors.forename: Paul
authors.initials: P
authors.lastname: Krimpenfort
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Michalak
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002678:Chimera; D002999:Clone Cells; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D042822:Genomic Instability; D005838:Genotype; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009857:Oncogenes; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism; D011786:Quality Control; D015203:Reproducibility of Results; D055752:Small Cell Lung Carcinoma / Q000378:metabolism / Q000473:pathology
chemical_list: D008156:Luciferases; D004254:DNA Nucleotidyltransferases; C045119:FLP recombinase