Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase

DuPage, Michel; Dooley, Alison; Jacks, Tyler

doi:10.1038/nprot.2009.95

Cited by 775 publications

(907 citation statements)

References 33 publications

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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%

“…A Cre recombinase‐inducible mutant Kras G12D allele was specifically activated in lungs by inhalation of Cre adenovirus (DuPage et al ., 2009) to study age‐associated differences in lung tumor formation. KRAS mutations represent potent oncogenic driver events that occur in 35% of lung cancers and 30% of all human cancers (Wilson & Tolias, 2016).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

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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“…Autochthonous K-ras G12D/WT ; p53 −/− lung tumors and derivative cell lines Lung tumors were initiated via intratracheal delivery of Lenti-Cre or Adeno-Cre in K-ras LSL-G12D/WT ; p53 flox/flox mice as described previously (DuPage et al 2009). The Massachusetts Institute of Technology Institutional Animal Care and Use Committee approved all animal studies and procedures.…”

Section: Methodsmentioning

confidence: 99%

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

Gocheva

Oudin

et al. 2015

Genes Dev.

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Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastatic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program. These three lineage-specific transcription factors are consistently down-regulated in metastatic cells compared with nonmetastatic cells. Knockdown of these three factors acts synergistically and is sufficient to promote the metastatic potential of nonmetastatic cells to that of naturally arising metastatic cells in vivo. Furthermore, silencing of these three transcription factors is sufficient to account for a significant fraction of the gene expression differences between the nonmetastatic and metastatic states in lung adenocarcinoma, including up-regulated expression of the invadopodia component Tks5 long , the embryonal protooncogene Hmga2, and the epithelial-to-mesenchymal mediator Snail. Finally, analyses of tumors from a genetically engineered mouse model and patients show that low expression of Nkx2-1, Foxa2, and Cdx2 strongly correlates with more advanced tumors and worse survival. Our findings reveal that a large part of the complex transcriptional network in metastasis can be controlled by a small number of regulatory nodes that function redundantly, and loss of multiple nodes is required to fully activate the metastatic program.[Keywords: lung adenocarcinoma; metastasis; Nkx2-1; Foxa2; Cdx2; genetically engineered mouse model of cancer] Supplemental material is available for this article.

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“…After Ad-Cre-mediated recombination, mice were generated with lung cells that carried the K-ras mutation and were homozygous (i.e., KO), heterozygous, and WT at the Dnmt3a locus. Ad-Cre (Gene Transfer Vector Core, University of Iowa) was delivered via an intratracheal approach (22). Briefly, 8-to 12-wk-old mice were anesthetized by i.p.…”

Section: Methodsmentioning

confidence: 99%

“…1A). Oncogene activation and Dnmt3a deletion were induced by intratracheal infusion with adenoviral Cre recombinase (Ad-Cre) (22).…”

Section: Dnmt3amentioning

confidence: 99%

Deletion of the de novo DNA methyltransferase Dnmt3a promotes lung tumor progression

Gao

Steine

Barrasa

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

118

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Alterations in DNA methylation have been associated with genome-wide hypomethylation and regional de novo methylation in numerous cancers. De novo methylation is mediated by the de novo methyltransferases Dnmt3a and 3b, but only Dnmt3b has been implicated in promoting cancer by silencing of tumor-suppressor genes. In this study, we have analyzed the role of Dnmt3a in lung cancer by using a conditional mouse tumor model. We show that Dnmt3a deficiency significantly promotes tumor growth and progression but not initiation. Changes in gene expression show that Dnmt3a deficiency affects key steps in cancer progression, such as angiogenesis, cell adhesion, and cell motion, consistent with accelerated and more malignant growth. Our results suggest that Dnmt3a may act like a tumor-suppressor gene in lung tumor progression and may be a critical determinant of lung cancer malignancy.adenocarcinoma | cancer epigenetics | gene body methylation | K-ras

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Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase

Cited by 775 publications

References 33 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

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis

Deletion of the de novo DNA methyltransferase Dnmt3a promotes lung tumor progression

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