Premalignant lesions of the bronchial epithelium
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE81819 | GEO | 2016/05/25
SECONDARY ACCESSION(S): PRJNA322627
REPOSITORIES: GEO
Similar Datasets
Project description:Exposure to cigarette smoke creates a field of injury throughout the entire respiratory tract inducing genomic alterations that lead to an “at-risk” airway where and lung cancers develop. Lung squamous cell carcinoma (SCC) arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions(PMLs). The presence of high-grade persistent or progressive PMLs is a marker of increased lung cancer risk both at the lesion site elsewhere in the lung. Effective tools to identify and treat premalignant lesions at highest risk of progression to invasive carcinoma are lacking. We profiled via RNA-Seq airway brushing and biopsies (divided into two cohorts: discovery and validation) obtained from high-risk smokers undergoing lung cancer screening via serial auto-fluorescence bronchoscopy procedures. We identified four distinct molecular subtypes (Proliferative, Inflammatory, Secretory, and Normal) in the bronchial biopsies that correspond to a spectrum of biological and morphological alterations. The Proliferative subtype was enriched with dysplastic PMLs from current smokers that exhibit up-regulation of KRT5 and KI67 as well as metabolic and cell cycle pathways, and down-regulation of cilium-associated processes and FOXJ1 expression. Molecular subtype classification in the validation cohort biopsies replicated these significant clinical and biological associations. Airway brushes from normal fluorescing areas of the large airway classified as the Proliferative subtype specifically predicts the presence of biopsies of this same subtype. Within the Proliferative subtype, genes associated with interferon signaling and antigen processing and presentation were observed to be down-regulated among dysplastic biopsies that persistent or progress in the future. Innate and adaptive immune cells were computationally predicted to be depleted in these biopsies and this was confirmed via immunofluorescence staining of adjacent biopsies. These findings provide a proof of concept that molecular biomarkers of endobronchial biopsies can enhance histopathological grading and that immunoprevention strategies are an important future direction in intercepting the progression of PMLs to lung cancer.
2019-03-05 | GSE109743 | GEO
Project description:Premalignant lesions of the bronchial epithelium
| PRJNA322627 | ENA
Project description:Bronchial premalignant lesions have distinct molecular subtypes associated with future histologic progression
| PRJNA431899 | ENA
Project description:The human bronchial epithelium is composed of multiple, distinct cell types that cooperate to defend against environmental insults. While studies have shown that smoking alters bronchial epithelial function and morphology, its precise effects on specific cell types and overall tissue composition are unclear. We used single-cell RNA sequencing to profile bronchial epithelial cells from six never- and six current smokers. Unsupervised analyses led to the characterization of a set of toxin metabolism genes that localized to smoker ciliated cells, tissue remodeling associated with a loss of club cells and extensive goblet cell hyperplasia, and a novel peri-goblet epithelial subpopulation in smokers that expressed a marker of bronchial premalignant lesions. Our data demonstrates that smoke exposure drives a complex landscape of cellular alterations that may prime the human bronchial epithelium for disease.
2019-09-27 | GSE131391 | GEO
Project description:Lung squamous cell carcinoma (SCC) is thought to arise from premalignant lesions in the airway epithelium, therefore studying these lesions is critical for understanding lung carcinogenesis. We performed RNA sequencing on laser-microdissected representative cell populations along the SCC pathological continuum of patient-matched normal basal cells, premalignant lesions, and tumor cells. We discovered transcriptomic changes and identified genomic pathways altered with initiation and progression of SCC within individual patients. We used immunofluorescent staining to confirm gene expression changes in premalignant lesions and tumor cells, including increased expression of SLC2A1, CEACAM5, and PTBP3 at the protein level and increased activation of MYC via nuclear translocation. Cytoband enrichment analysis revealed coordinated loss and gain of expression in chromosome 3p and 3q regions, respectively, during carcinogenesis. This is the first gene expression profiling of airway premalignant lesions with patient-matched samples that provides insight into the mechanisms of stepwise lung carcinogenesis. Profiling of mRNA expression in laser-microdissected normal airway basal cells, premalignant airway lesions, and lung SCC tumor cells by massively parallel RNA sequencing.
2014-07-03 | E-GEOD-49155 | biostudies-arrayexpress
Project description:Lung squamous cell carcinoma (SCC) is thought to arise from premalignant lesions in the airway epithelium, therefore studying these lesions is critical for understanding lung carcinogenesis. We performed RNA sequencing on laser-microdissected representative cell populations along the SCC pathological continuum of patient-matched normal basal cells, premalignant lesions, and tumor cells. We discovered transcriptomic changes and identified genomic pathways altered with initiation and progression of SCC within individual patients. We used immunofluorescent staining to confirm gene expression changes in premalignant lesions and tumor cells, including increased expression of SLC2A1, CEACAM5, and PTBP3 at the protein level and increased activation of MYC via nuclear translocation. Cytoband enrichment analysis revealed coordinated loss and gain of expression in chromosome 3p and 3q regions, respectively, during carcinogenesis. This is the first gene expression profiling of airway premalignant lesions with patient-matched samples that provides insight into the mechanisms of stepwise lung carcinogenesis.
2014-07-03 | GSE49155 | GEO
Project description:Bronchial premalignant lesions (PMLs) are composed of expanding bronchial basal cells that can progress to lung squamous cell carcinoma (LUSC) by evading immune responses. Despite ongoing efforts that have mapped gene expression and cell diversity across bronchial PML pathologies, signaling and transcriptional events driving malignancy are poorly understood. Evidence has suggested key roles for the Hippo pathway effectors YAP and TAZ and associated TEAD and TP63 transcription factor families in bronchial basal cell biology and LUSC. In this study we mapped target genes regulated by these factors by combined RNA-seq and ChIP-seq in primary human bronchial epithelial cells, revealing a converged transcriptional network that is strongly associated with bronchial PML progression. Our observations suggest that YAP/TAZ-TEAD-TP63 associate to cooperatively promote basal cell proliferation and repress signals associated with interferon responses and immune cell communication. Directly repressed targets include MHC Class II factors expressed in bronchial epithelium that correlate with adaptive immune Th1 cell activities known to contribute to the immunosuppressive microenvironment in lung cancers. Our findings provide a molecular mechanism for gene regulation in progressive PMLs that contributes to immune evasion, offering potential new avenues for lung cancer interception.
2023-05-09 | GSE213655 | GEO
Project description:Bronchial premalignant lesions (PMLs) are composed of expanding bronchial basal cells that can progress to lung squamous cell carcinoma (LUSC) by evading immune responses. Despite ongoing efforts that have mapped gene expression and cell diversity across bronchial PML pathologies, signaling and transcriptional events driving malignancy are poorly understood. Evidence has suggested key roles for the Hippo pathway effectors YAP and TAZ and associated TEAD and TP63 transcription factor families in bronchial basal cell biology and LUSC. In this study we mapped target genes regulated by these factors by combined RNA-seq and ChIP-seq in primary human bronchial epithelial cells, revealing a converged transcriptional network that is strongly associated with bronchial PML progression. Our observations suggest that YAP/TAZ-TEAD-TP63 associate to cooperatively promote basal cell proliferation and repress signals associated with interferon responses and immune cell communication. Directly repressed targets include MHC Class II factors expressed in bronchial epithelium that correlate with adaptive immune Th1 cell activities known to contribute to the immunosuppressive microenvironment in lung cancers. Our findings provide a molecular mechanism for gene regulation in progressive PMLs that contributes to immune evasion, offering potential new avenues for lung cancer interception.
2023-05-09 | GSE213654 | GEO
Project description:Cigarette smoking is the main risk factor for the development of squamous cell lung carcinoma (SCC). However, the smoking-related molecular changes in SCC have not been studied. We wanted to identify genes in both histologically normal bronchial epithelium and SCC samples that are differentially expressed between current and ex-smokers. In addition, to analyze the levels of the smoking-related genes identified in normal bronchial epithelium with the levels in SCC. Gene expression profiles were generated using Agilent whole human genome microarrays in 28 laser microdissected normal bronchus epithelial samples and in 35 laser microdissected SCC samples of current and ex-smokers. Levels of 246 genes, mainly related to oxidative stress response, were significantly different between normal bronchial epithelium of current and ex-smokers. No significant differences were associated with the smoking status in SCC samples. Analysis of the 246 smoking specific genes in SSC from current and ex-smokers also revealed no differences. As a next step, we compared the levels of the smoking-specific gene signature between normal bronchial epithelium from ex- and current smokers to all 34 SCC samples. Twenty-two percent of the upregulated genes are further upregulated in SCC as compared to current smokers. Expression of the downregulated genes was even further downregulated for 79% of the genes in SCC as compared to bronchus epithelium of current smokers. The downregulated genes included several tumour suppressor genes. This study shows that genes upregulated in normal bronchial epithelium of current smokers are expressed at similar levels in SCC samples, while levels of downregulated genes were significantly further reduced in SCC. This indicates that these downregulated genes play a role in SCC oncogenesis.
2008-10-01 | GSE12428 | GEO
Project description:SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in the airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments have not been fully characterized using matched samples from large cohorts. Gene expression data from 793 nasal and 1673 bronchial brushes obtained from individuals participating in lung cancer screening or diagnostic workup revealed that smoking status (current versus former) was the only clinical factor significantly and reproducibly associated with VE gene expression. The expression of ACE2 and TMPRSS2 was higher in smokers in the bronchus but not in the nose. AQ1 scRNA-seq of nasal brushings indicated that ACE2 co-expressed genes were highly expressed in club and C15orf48 secretory cells while TMPRSS2 co-expressed genes were highly expressed in keratinizing epithelial cells. In contrast, these ACE2 and TMPRSS2 modules were highly expressed in goblet cells in scRNA-seq from bronchial brushings. Cell-type deconvolution of the gene expression data confirmed that smoking increased the abundance of several secretory cell populations in the bronchus, but only goblet cells in the nose. The association of ACE2 and TMPRSS2 with smoking in the bronchus is due to their high expression in goblet cells which increase in abundance in current smoker airways. In contrast, in the nose, these genes are not predominantly expressed in cell populations modulated by smoking. In individuals with elevated lung cancer risk, smokinginduced VE gene expression changes in the nose likely have minimal impact on SARS-CoV-2 infection, but in the bronchus, smoking may lead to higher viral loads and more severe disease.
2022-10-25 | GSE210659 | GEO