scholarly journals Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model

2014 ◽  
Vol 7 (2) ◽  
pp. 73-84 ◽  
Author(s):  
Karsta Luettich ◽  
Yang Xiang ◽  
Anita Iskandar ◽  
Alain Sewer ◽  
Florian Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Cigarette Smoke ◽  
Lung Tumor ◽  
Immune Surveillance ◽  
Gene Expression Signature ◽  
Chemical Carcinogenesis ◽  
Lung Tumors ◽  
Whole Body ◽  
Significant Differential Expression

ABSTRACT The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening model in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops lung tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smokerelated lung tumors in the A/J mouse model using mRNA and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression interaction term analysis of lung tumors and surrounding nontumorous parenchyma samples from animals that were exposed to either 300 mg/m3 MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis® (IPA®) indicated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism and a deregulation of potentially oncogenic miRNA in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA, which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene expression signature and show its utility in distinguishing between cigarette smoke-related and spontaneous lung tumors

scholarly journals A shared gene expression signature in mouse models of EBV-associated and non–EBV-associated Burkitt lymphoma

Blood ◽  
2011 ◽  
Vol 118 (26) ◽  
pp. 6849-6859 ◽  
Author(s):  
Kathryn T. Bieging ◽  
Kamonwan Fish ◽  
Subbarao Bondada ◽  
Richard Longnecker
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Mouse Model ◽  
Tumor Cells ◽  
Burkitt Lymphoma ◽  
Gene Expression Signature ◽  
Differentially Expressed ◽  
Cell Phenotype ◽  
Phenotypic Differences ◽  
Tumor Onset

AbstractThe link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional profiles of tumor cells from LMP2A/λ-MYC and λ-MYC mice are strikingly similar, with fewer than 20 genes differentially expressed. We evaluated the functional significance of one of the most interesting differentially expressed genes, Egr1, and found that it was not required for acceleration of tumor onset by LMP2A. Our studies demonstrate the remarkable ability of LMP2A to affect the pretumor B-cell phenotype and tumorigenesis without substantially altering gene expression in tumor cells.

scholarly journals Gene expression signature of cerebellar hypoplasia in a mouse model of Down syndrome during postnatal development

BMC Genomics ◽  
2009 ◽  
Vol 10 (1) ◽  
pp. 138 ◽  
Author(s):  
Julien Laffaire ◽  
Isabelle Rivals ◽  
Luce Dauphinot ◽  
Fabien Pasteau ◽  
Rosine Wehrle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Down Syndrome ◽  
Mouse Model ◽  
Postnatal Development ◽  
Gene Expression Signature ◽  
Cerebellar Hypoplasia ◽  
Expression Signature

scholarly journals Cigarette exposure induces changes in maternal vascular function in a pregnant mouse model

2010 ◽  
Vol 298 (5) ◽  
pp. R1249-R1256 ◽  
Author(s):  
Robin E. Gandley ◽  
Arun Jeyabalan ◽  
Ketaki Desai ◽  
Stacy McGonigal ◽  
Jennifer Rohland ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cigarette Smoke ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Smoke Exposure ◽  
Renal Arteries ◽  
Growth Restriction ◽  
Whole Body ◽  
Cigarette Smoke Exposure ◽  
Pregnant Mice

Smoking is associated with multiple adverse pregnancy outcomes, including fetal growth restriction. The objective of this study was to determine whether cigarette smoke exposure during pregnancy in a mouse model affects the functional properties of maternal uterine, mesenteric, and renal arteries as a possible mechanism for growth restriction. C57Bl/CJ mice were exposed to whole body sidestream smoke for 4 h/day. Smoke particle exposure was increased from day 4 of gestation until late pregnancy ( day 16–19), with mean total suspended particle levels of 63 mg/m3, representative of moderate-to-heavy smoking in humans. Uterine, mesenteric, and renal arteries from late-pregnant and virgin mice were isolated and studied in a pressure-arteriograph system ( n = 23). Plasma cotinine was measured by ELISA. Fetal weights were significantly reduced in smoke-exposed compared with control fetuses (0.88 ± 0.1 vs. 1.0 ± 0.08 g, P < 0.02), while litter sizes were not different. Endothelium-mediated relaxation responses to methacholine were significantly impaired in both the uterine and mesenteric vasculature of pregnant mice exposed to cigarette smoke during gestation. This difference was not apparent in isolated renal arteries from pregnant mice exposed to cigarette smoke; however, relaxation was significantly reduced in renal arteries from smoke-exposed virgin mice. In conclusion, we found that passive cigarette smoke exposure is associated with impaired vascular relaxation of uterine and mesenteric arteries in pregnant mice. Functional maternal vascular perturbations during pregnancy, specifically impaired peripheral and uterine vasodilation, may contribute to a mechanism by which smoking results in fetal growth restriction.

Validation of the Lung Subtyping Panel in Multiple Fresh-Frozen and Formalin-Fixed, Paraffin-Embedded Lung Tumor Gene Expression Data Sets

2015 ◽  
Vol 140 (6) ◽  
pp. 536-542 ◽  
Author(s):  
Hawazin Faruki ◽  
Gregory M. Mayhew ◽  
Cheng Fan ◽  
Matthew D. Wilkerson ◽  
Scott Parker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Lung Tumor ◽  
Gene Expression Signature ◽  
Data Sets ◽  
Expression Data ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Fresh Frozen ◽  
Formalin Fixed

Context A histologic classification of lung cancer subtypes is essential in guiding therapeutic management. Objective To complement morphology-based classification of lung tumors, a previously developed lung subtyping panel (LSP) of 57 genes was tested using multiple public fresh-frozen gene-expression data sets and a prospectively collected set of formalin-fixed, paraffin-embedded lung tumor samples. Design The LSP gene-expression signature was evaluated in multiple lung cancer gene-expression data sets totaling 2177 patients collected from 4 platforms: Illumina RNAseq (San Diego, California), Agilent (Santa Clara, California) and Affymetrix (Santa Clara) microarrays, and quantitative reverse transcription–polymerase chain reaction. Gene centroids were calculated for each of 3 genomic-defined subtypes: adenocarcinoma, squamous cell carcinoma, and neuroendocrine, the latter of which encompassed both small cell carcinoma and carcinoid. Classification by LSP into 3 subtypes was evaluated in both fresh-frozen and formalin-fixed, paraffin-embedded tumor samples, and agreement with the original morphology-based diagnosis was determined. Results The LSP-based classifications demonstrated overall agreement with the original clinical diagnosis ranging from 78% (251 of 322) to 91% (492 of 538 and 869 of 951) in the fresh-frozen public data sets and 84% (65 of 77) in the formalin-fixed, paraffin-embedded data set. The LSP performance was independent of tissue-preservation method and gene-expression platform. Secondary, blinded pathology review of formalin-fixed, paraffin-embedded samples demonstrated concordance of 82% (63 of 77) with the original morphology diagnosis. Conclusions The LSP gene-expression signature is a reproducible and objective method for classifying lung tumors and demonstrates good concordance with morphology-based classification across multiple data sets. The LSP panel can supplement morphologic assessment of lung cancers, particularly when classification by standard methods is challenging.

scholarly journals Discriminating Spontaneous From Cigarette Smoke and THS 2.2 Aerosol Exposure-Related Proliferative Lung Lesions in A/J Mice by Using Gene Expression and Mutation Spectrum Data

2021 ◽  
Vol 3 ◽  
Author(s):  
Yang Xiang ◽  
Karsta Luettich ◽  
Florian Martin ◽  
James N. D. Battey ◽  
Keyur Trivedi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cigarette Smoke ◽  
Human Lung ◽  
Gene Signature ◽  
Lung Tumors ◽  
Tumor Classification ◽  
Spontaneous Tumors ◽  
Data Set ◽  
Inhalation Study ◽  
The Impact

Mice, especially A/J mice, have been widely employed to elucidate the underlying mechanisms of lung tumor formation and progression and to derive human-relevant modes of action. Cigarette smoke (CS) exposure induces tumors in the lungs; but, non-exposed A/J mice will also develop lung tumors spontaneously with age, which raises the question of discriminating CS-related lung tumors from spontaneous ones. However, the challenge is that spontaneous tumors are histologically indistinguishable from the tumors occurring in CS-exposed mice. We conducted an 18-month inhalation study in A/J mice to assess the impact of lifetime exposure to Tobacco Heating System (THS) 2.2 aerosol relative to exposure to 3R4F cigarette smoke (CS) on toxicity and carcinogenicity endpoints. To tackle the above challenge, a 13-gene gene signature was developed based on an independent A/J mouse CS exposure study, following by a one-class classifier development based on the current study. Identifying gene signature in one data set and building classifier in another data set addresses the feature/gene selection bias which is a well-known problem in literature. Applied to data from this study, this gene signature classifier distinguished tumors in CS-exposed animals from spontaneous tumors. Lung tumors from THS 2.2 aerosol-exposed mice were significantly different from those of CS-exposed mice but not from spontaneous tumors. The signature was also applied to human lung adenocarcinoma gene expression data (from The Cancer Genome Atlas) and discriminated cancers in never-smokers from those in ever-smokers, suggesting translatability of our signature genes from mice to humans. A possible application of this gene signature is to discriminate lung cancer patients who may benefit from specific treatments (i.e., EGFR tyrosine kinase inhibitors). Mutational spectra from a subset of samples were also utilized for tumor classification, yielding similar results. “Landscaping” the molecular features of A/J mouse lung tumors highlighted, for the first time, a number of events that are also known to play a role in human lung tumorigenesis, such as Lrp1b mutation and Ros1 overexpression. This study shows that omics and computational tools provide useful means of tumor classification where histopathological evaluation alone may be unsatisfactory to distinguish between age- and exposure-related lung tumors.

scholarly journals Down-regulation of A20 promotes immune escape of lung adenocarcinomas

2021 ◽  
Vol 13 (601) ◽  
pp. eabc3911
Author(s):  
Kristina Breitenecker ◽  
Monika Homolya ◽  
Andreea C. Luca ◽  
Veronika Lang ◽  
Christoph Trenk ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Escape ◽  
Cytotoxic T Cells ◽  
Immune Surveillance ◽  
Gene Expression Signature ◽  
Lung Tumors ◽  
Immune Checkpoint Blockade ◽  
Loss Of Function ◽  
Lung Tumorigenesis ◽  
Necrosis Factor Alpha

Inflammation is a well-known driver of lung tumorigenesis. One strategy by which tumor cells escape tight homeostatic control is by decreasing the expression of the potent anti-inflammatory protein tumor necrosis factor alpha–induced protein 3 (TNFAIP3), also known as A20. We observed that tumor cell intrinsic loss of A20 markedly enhanced lung tumorigenesis and was associated with reduced CD8+ T cell–mediated immune surveillance in patients with lung cancer and in mouse models. In mice, we observed that this effect was completely dependent on increased cellular sensitivity to interferon-γ (IFN-γ) signaling by aberrant activation of TANK-binding kinase 1 (TBK1) and increased downstream expression and activation of signal transducer and activator of transcription 1 (STAT1). Interrupting this autocrine feed forward loop by knocking out IFN-α/β receptor completely restored infiltration of cytotoxic T cells and rescued loss of A20 depending tumorigenesis. Downstream of STAT1, programmed death ligand 1 (PD-L1) was highly expressed in A20 knockout lung tumors. Accordingly, immune checkpoint blockade (ICB) treatment was highly efficient in mice harboring A20-deficient lung tumors. Furthermore, an A20 loss-of-function gene expression signature positively correlated with survival of melanoma patients treated with anti–programmed cell death protein 1. Together, we have identified A20 as a master immune checkpoint regulating the TBK1–STAT1–PD-L1 axis that may be exploited to improve ICB therapy in patients with lung adenocarcinoma.

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