Knock-in of oncogenic Kras does not transform mouse somatic cells but triggers a transcriptional response that classifies human cancers
- PMID: 17875685
- DOI: 10.1158/0008-5472.CAN-07-1126
Knock-in of oncogenic Kras does not transform mouse somatic cells but triggers a transcriptional response that classifies human cancers
Abstract
KRAS mutations are present at a high frequency in human cancers. The development of therapies targeting mutated KRAS requires cellular and animal preclinical models. We exploited adeno-associated virus-mediated homologous recombination to insert the Kras G12D allele in the genome of mouse somatic cells. Heterozygous mutant cells displayed a constitutively active Kras protein, marked morphologic changes, increased proliferation and motility but were not transformed. On the contrary, mouse cells in which we overexpressed the corresponding Kras cDNA were readily transformed. The levels of Kras activation in knock-in cells were comparable with those present in human cancer cells carrying the corresponding mutation. Kras-mutated cells were compared with their wild-type counterparts by gene expression profiling, leading to the definition of a "mutated Kras-KI signature" of 345 genes. This signature was capable of classifying mouse and human cancers according to their KRAS mutational status, with an accuracy similar to or better than published Ras signatures. The isogenic cells that we have developed recapitulate the oncogenic activation of KRAS occurring in cancer and represent new models for studying Kras-mediated transformation. Our results have implications for the identification of human tumors in which the oncogenic KRAS transcriptional response is activated and suggest new strategies to build mouse models of tumor progression.
Similar articles
-
Knock-in of mutant K-ras in nontumorigenic human epithelial cells as a new model for studying K-ras mediated transformation.Cancer Res. 2007 Sep 15;67(18):8460-7. doi: 10.1158/0008-5472.CAN-07-0108. Cancer Res. 2007. PMID: 17875684
-
Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice.Cancer Res. 2003 May 1;63(9):2016-9. Cancer Res. 2003. PMID: 12727811
-
Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene.J Natl Cancer Inst. 2007 Nov 21;99(22):1668-82. doi: 10.1093/jnci/djm208. Epub 2007 Nov 13. J Natl Cancer Inst. 2007. PMID: 18000218
-
Transgenic mouse models of human gastric and hepatic carcinomas.Semin Cancer Biol. 1994 Feb;5(1):61-8. Semin Cancer Biol. 1994. PMID: 8186389 Review.
-
Mouse models for human lung cancer.Genes Dev. 2005 Mar 15;19(6):643-64. doi: 10.1101/gad.1284505. Genes Dev. 2005. PMID: 15769940 Review.
Cited by
-
Oncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway.Oncotarget. 2015 May 10;6(13):10994-1008. doi: 10.18632/oncotarget.3552. Oncotarget. 2015. PMID: 26028667 Free PMC article.
-
Low-frequency KRAS mutations are prevalent in lung adenocarcinomas.Per Med. 2015 Mar;12(2):83-98. doi: 10.2217/pme.14.69. Per Med. 2015. PMID: 27795727 Free PMC article.
-
Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.Nat Commun. 2016 Jun 20;7:11971. doi: 10.1038/ncomms11971. Nat Commun. 2016. PMID: 27321283 Free PMC article.
-
Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses.Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20864-9. doi: 10.1073/pnas.0808757105. Epub 2008 Dec 23. Proc Natl Acad Sci U S A. 2008. PMID: 19106301 Free PMC article.
-
Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells.J Biol Chem. 2024 Jun;300(6):107409. doi: 10.1016/j.jbc.2024.107409. Epub 2024 May 23. J Biol Chem. 2024. PMID: 38796063 Free PMC article.
Publication types
MeSH terms
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous
