Analysis of lung tumor initiation and progression using conditional expression of oncogenic <i>K-ras</i>

Jackson, Erica; Willis, Nicholas A.; Mercer, Kim L.; Bronson, Roderick T.; Crowley, Denise; Montoya, Raymond; Jacks, Tyler; Tuveson, David A.

doi:10.1101/gad.943001

Cited by 1,770 publications

(1,958 citation statements)

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“…Lungs from Cre adenovirus‐instilled Kras G12D mice showed hyperproliferation leading to different grades of lung lesions previously reported in mouse lung tumor models (Jackson et al ., 2001; DuPage et al ., 2009) such as bronchioloalveolar hyperplasia, adenoma, and adenocarcinoma (Fig. 1C, Methods S1).…”

Section: Resultsmentioning

confidence: 99%

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

et al. 2017

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SummaryAging is often accompanied by a dramatic increase in cancer susceptibility. To gain insights into how aging affects tumor susceptibility, we generated a conditional mouse model in which oncogenic Kras G12D was activated specifically in lungs of young (3–5 months) and old (19–24 months) mice. Activation of Kras G12D in old mice resulted in shorter survival and development of higher‐grade lung tumors. Six weeks after Kras G12D activation, old lung tissues contained higher numbers of adenomas than their young tissue counterparts. Lung tumors in old mice displayed higher proliferation rates, as well as attenuated DNA damage and p53 tumor suppressor responses. Gene expression comparison of lung tumors from young and old mice revealed upregulation of extracellular matrix‐related genes in young tumors, indicative of a robust cancer‐associated fibroblast response. In old tumors, numerous inflammation‐related genes such as Ccl7,IL‐1β, Cxcr6, and IL‐15ra were consistently upregulated. Increased numbers of immune cells were localized around the periphery of lung adenomas from old mice. Our experiments indicate that more aggressive lung tumor formation in older Kras G12D mice may be in part the result of subdued tumor suppressor and DNA damage responses, an enhanced inflammatory milieu, and a more accommodating tissue microenvironment.

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Section: Resultsmentioning

confidence: 99%

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

et al. 2017

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“…We generated a cohort of conditional mutant mice by crossing Lox-Stop-Lox (LSL)-K-ras G12D mice (Jackson et al, 2001) to CC10-Cre mice in which Cre recombinase expression is under control of the Clara cell secretory protein promoter. As with other transgenes driven by CC10 (Perl et al, 2002), Cre expression was limited to the lung bronchiolar epithelium as demonstrated by analysis of the CC10-Cre strain crossed with the ROSA-Stop-LacZ reporter strain (data not shown), which demonstrated the complete absence of LacZ staining beyond the bronchoalveolar duct junction.…”

Section: Cc10-cre/lsl-k-ras G12d Conditional Mutant Mice Develop Lungmentioning

confidence: 99%

K-ras activation generates an inflammatory response in lung tumors

et al. 2005

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Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras G12D alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.

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“…Of these, only Kras2 is a known target of mutation in lung tumors 3,4 , and mice expressing oncogenic Kras2 have a high incidence of early onset lung cancer 7,8 . Lung tumors from F1-hybrid mice showed a strong bias for Kras2 mutation involving the allele inherited from the more susceptible parent 9 , rendering Kras2 a candidate for Pas1.…”

Section: Introductionmentioning

confidence: 99%

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

Pérez-Losada

Mao

et al. 2006

Nat Genet

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Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1), spanning a region containing six genes 2 , one of which is Kras2. Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors 3,4 , and is a candidate Pas1 gene 5 . M. spretus mice (SPRET) carry a Pas1 resistance haplotype for chemically induced lung tumors 6 . We demonstrate here that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele in Kras2 LA2 mice. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events, and could have major implications for the design of human association studies to identify cancer susceptibility genes. KeywordsLung Cancer; Pas-1; Susceptibility; Kras2The critical Pas1 interval encompasses Bcat1, Lrmp, Las1, Ghiso, Kras2,. Of these, only Kras2 is a known target of mutation in lung tumors 3,4 , and mice expressing oncogenic Kras2 have a high incidence of early onset lung cancer 7,8 . Lung tumors from F1-hybrid mice showed a strong bias for Kras2 mutation involving the allele inherited from the more susceptible parent 9 , rendering Kras2 a candidate for Pas1. However, no coding sequence differences in Kras2 have been detected among all mouse strains studied, and the possible mechanisms by which Kras2 may contribute to the effect of Pas1 remain unclear, causing some investigators to focus on other genes in the Pas1 region COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. hybrids generated between Kras2 LA2 FVB/N and SPRET/Ei had relatively low tumor incidence and number at 6 months ( Fig. 1a), and some animals survived well over one year without becoming moribund. HHS Public AccessWe mated female FVBSPRETF1 hybrids with male Kras2 LA2 FVB/N mice to generate a large population of interspecific backcross mice. A total of 224 (FVBSPRETF1)FVBKras2 LA2 backcross mice were aged to 6 months, and sacrificed for assessment of tumor number. The distribution of tumor number was very wide (Fig. 1a), in agreement with the observation that there are many lung tumor susceptibility/resistance loci 15,16 . These animals were genotyped using markers on chromosome 6 to test for linkage to Pas1. We initially envisaged two possible outcomes: (i) If Kras2 is the Pas1 gene, there should be no linkage to the region, as every mouse carries the same parental mutant allele. This would be compatible with a mechanism in which selection for a more highly active or highly expressed Kras2 mutant allele in chemical carcinogenesis studies accounts completely for the effect of Pas1 (ref. 9). (ii) IfPas1 is a different gene(s) in the regi...

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Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras

Cited by 1,770 publications

References 19 publications

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

K-ras activation generates an inflammatory response in lung tumors

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

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