Transcription profiling of human lung adenocarcinoma and a carcinogen-induced mouse model
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Stearman RS
PROVIDER: S-ECPF-GEOD-2514 | biostudies-other | 2005 Dec
REPOSITORIES: biostudies-other
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Project description:Lung tumors
2007-07-20 | E-GEOD-2514 | biostudies-arrayexpress
Project description:Human lung adenocarcinoma (LUAD) in current or former smokers exhibits a high tumor mutational burden (TMB) and distinct mutational signatures. Syngeneic mouse models of clinically relevant smoking-related LUAD are lacking. We established and characterized a tobacco-associated, transplantable murine LUAD cell line, designated FVBW-17, from a LUAD induced by the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone in the FVB/N mouse strain. Whole-exome sequencing of FVBW-17 cells identified tobacco-associated KrasG12D and Trp53 mutations and a similar mutation profile to that of classic alkylating agents with a TMB greater than 500. FVBW-17 cells transplanted subcutaneously, via tail vein, and orthotopically generated tumors that were histologically similar to human LUAD in FVB/N mice. FVBW-17 tumors expressed programmed death ligand 1 (PD-L1), were infiltrated with CD8+ T cells, and were responsive to anti-PD-L1 therapy. FVBW-17 cells were also engineered to express green fluorescent protein and luciferase to facilitate detection and quantification of tumor growth. Distant metastases to lung, spleen, liver, and kidney were observed from subcutaneously transplanted tumors. This potentially novel cell line is a robust representation of human smoking-related LUAD biology and provides a much needed preclinical model in which to test promising new agents and combinations, including immune-based therapies.
| S-EPMC7934870 | biostudies-literature
Project description:Cigarette smoke (CS) contains hundreds of carcinogens and is a potent inducer of oxidative and bulky DNA damage, which when insufficiently repaired leads to activation of DNA damage response and possibly mutations. The DNA repair protein xeroderma pigmentosum group C (XPC) is primed to play an important role in CS-induced DNA damage because of its function in initiating repair of both bulky oxidative DNA damage. We hypothesized that loss of XPC function will increase susceptibility to developing CS- and carcinogen-induced lung cancer through impaired repair of oxidative DNA damage. Mice deficient in XPC (XPC-/-) exposed to chronic CS developed lung tumors whereas their wild-type littermates (XPC+/+) did not. XPC-/- mice treated with the CS-carcinogen urethane developed lung adenocarcinomas representing progressive stages of tumor development, with lung tumor number increased 17-fold compared with XPC+/+ mice. Mice heterozygous for XPC (XPC+/-) demonstrated a gene-dose effect, developing an intermediate number of lung tumors with urethane treatment. Treatment of XPC-/- mice with the carcinogen 3-methylcholanthrene followed by the proliferative agent butylated hydroxytoluene resulted in a 2-fold increase in lung adenocarcinoma development. Finally, tumor number decreased 7-fold in the lungs of XPC-/- mice by concurrent treatment with the antioxidant, N-acetylcysteine. Altogether, this supports a mechanism by which decreased XPC expression promotes lung adenocarcinoma development in response to CS-carcinogen exposure, due in part to impaired oxidative DNA damage repair.
| S-EPMC6514449 | biostudies-literature
Project description:Human adenocarcinoma (AC) is the most frequently diagnosed human lung cancer, and its absolute incidence is increasing dramatically. Compared to human lung AC, the A/J mouse-urethane model exhibits similar histological appearance and molecular changes. We examined the gene expression profiles of human and murine lung tissues (normal or AC) and compared the two species' datasets after aligning approximately 7500 orthologous genes. A list of 409 gene classifiers (P value <0.0001), common to both species (joint classifiers), showed significant, positive correlation in expression levels between the two species. A number of previously reported expression changes were recapitulated in both species, such as changes in glycolytic enzymes and cell-cycle proteins. Unexpectedly, joint classifiers in angiogenesis were uniformly down-regulated in tumor tissues. The eicosanoid pathway enzymes prostacyclin synthase (PGIS) and inducible prostaglandin E(2) synthase (PGES) were joint classifiers that showed opposite effects in lung AC (PGIS down-regulated; PGES up-regulated). Finally, tissue microarrays identified the same protein expression pattern for PGIS and PGES in 108 different non-small cell lung cancer biopsies, and the detection of PGIS had statistically significant prognostic value in patient survival. Thus, the A/J mouse-urethane model reflects significant molecular details of human lung AC, and comparison of changes in orthologous gene expression may provide novel insights into lung carcinogenesis.
| S-EPMC1613183 | biostudies-literature
Project description:The landscape of genetic alterations in disease models such as transgenic mice or mice with carcinogen-induced tumors has provided a huge amount of information that has shed light on the process of tumorigenesis in human non-small-cell lung cancer (NSCLC). We have previously identified stratifin (SFN) as a potent oncogene, and generated SFN-transgenic (Tg-SPC-SFN+/- ) mice, which express human SFN (hSFN) only in the lung. Here, we have found that carcinogen nicotine-derived nitrosaminoketone (NNK)-induced tumors developing in Tg-SPC-SFN+/- mice show a similar histology to human lung adenocarcinoma and exhibit high hSFN expression. In order to compare the genetic characteristics of Tg-SPC-SFN+/- tumors and human lung adenocarcinoma, the former were subjected to whole-exome sequencing. Interestingly, Tg-SPC-SFN+/- tumors showed the distinct distribution of exonic mutations and high number of mutated genes and transversion. Moreover, Tg-SPC-SFN+/- tumors showed 73 genes that were commonly detected in more than 2 tumors, mutations of which were also found in human lung adenocarcinoma. The expression levels of some of these genes were significantly associated with the clinical outcome of lung adenocarcinoma patients. Additionally, mutated genes in Tg-SPC-SFN+/- tumors were closely associated with key canonical pathways such as PI3K/AKT signaling and apoptosis signaling. These results suggest that SFN overexpression is a universal abnormality in human lung adenocarcinogenesis and Tg-SPC-SFN+/- tumors recapitulate key features of major human lung adenocarcinoma. Therefore, Tg-SPC-SFN+/- mice provide a useful model for clarifying the molecular mechanism underlying lung adenocarcinogenesis.
| S-EPMC6676126 | biostudies-literature
Project description:CYP2A13 is a human cytochrome P450 (P450) enzyme important in the bioactivation of the tobacco-specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). CYP2A13 expression levels vary dramatically among lung biopsy samples from patients, presumably owing in part to a suppression of CYP2A13 expression by disease-associated inflammation. Here, we determined whether CYP2A13 expression in the lungs of CYP2A13-humanized mice is suppressed by the presence of lung tumors. Tissues from an NNK lung tumor bioassay were examined. CYP2A13-humanized mice (95-100%) had multiple lung tumors at 16 weeks after NNK (30 or 50 mg/kg) treatment; whereas only ∼9% of saline-treated CYP2A13-humanized mice had lung tumor (∼1/lung). Mice with lung tumors, from the NNK-treated groups, were used for dissecting adjacent tumor-free lung tissues; whereas mice without visible lung tumors, from the saline-treated group, were used as controls. Compared with the controls, the levels of CYP2A13 protein and mRNA were both reduced significantly (by ≥50%) in the NNK-treated groups. The levels of mouse CYP2B10 and CYP2F2 mRNAs were also significantly lower in the dissected normal lung tissues from tumor-bearing mice than in lungs from the control mice. Pulmonary tissue levels of three proinflammatory cytokines, tumor necrosis factor alpha, interferon gamma, and interleukin-6, were significantly higher in the tumor-bearing mice than in the controls, indicating occurrence of low-grade lung inflammation at the time of necropsy. Taken together, these findings support the hypothesis that CYP2A13 levels in human lungs can be suppressed by disease-associated inflammation in tissue donors, a scenario causing underestimation of CYP2A13 levels in healthy lungs.
| S-EPMC4407704 | biostudies-literature
Project description:The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.
| S-EPMC5886988 | biostudies-literature
Project description:FVB, Balb/c, and C57BL/6 mice received the tobacco carcinogens urethane (Sigma Aldrich, U2500) intraperitoneally (1g/Kg in 100 μl phosphate-buffered saline) or diethylnitrosamine (200 mg/kg) (Sigma Aldrich, N0756). Carcinogen induced lung adenocarcinoma murine cell lines generation| Ten months post first carcinogen (urethane, DEN) exposure mice were sacrificed, lung tumours were dissected from surrounding healthy lung parenchyma under sterile conditions, were halved, one half was processed for histology and the other half was chopped into 1 mm pieces and seeded to cell culture dishes. Cells were cultured under standard conditions outlined below. When adenocarcinoma was diagnosed for a given tumour, its corresponding culture was passaged in vitro over a period of 18 months and 60 passages, whichever occurred first. After gene expression and mutational signature extraction, the signature were compared with human lung adenocarcinoma RNAseq results.
2022-10-24 | GSE126119 | GEO
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Project description:Effect of dexamethasone on gene expression in lung adenocarcinoma derived cell line A549
| S-ECPF-MEXP-2004 | biostudies-other