Bronchial premalignant lesions have distinct molecular subtypes associated with future histologic progression
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PROVIDER: PRJNA431899 | ENA |
REPOSITORIES: ENA
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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:Transcriptional profiling of hyperplastic, metaplastic, and dysplastic lesions of the bronchus in comparison with normal bronchial epithelium. The aim was to identify transcripts and cell signalling pathways associated with the development of isolated premalignant lesions and/or lesions combined with each other in the same bronchial epithelium.
2016-05-25 | GSE81819 | GEO
Project description:Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions
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Project description:Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions
| PRJNA927098 | ENA
Project description:Bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma, have distinct molecular subtypes. The proliferative subtype, enriched with bronchial dysplasia, had decreased expression of an antigen processing/presentation gene co-expression module in progressive/persistent versus regressive PMLs, suggesting a functional impact of these genes on immune evasion. Here, we performed miRNA sequencing, miRNA in situ hybridization (ISH), and spatial proteomics of bronchial biopsies from patients at high risk for lung cancer. A miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of the antigen presentation gene module. Staining on adjacent biopsy tissue showed that hsa-miR-149-5p was predominantly expressed in the epithelium and up-regulated in progressive/persistent proliferative lesions. Targets of this miRNA, the transcriptional coactivator of MHC-I gene expression, NLRC5, and the genes it regulates were down-regulated in these lesions. Decreased NLRC5 expression reduced both IFN-gamma induced MHC-I surface expression and CD8 T cell cytotoxicity in lung squamous cancer cells. In PMLs, basal cells with high levels of NLRC5 were in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in vivo. These findings indicate a functional role for hsa-miR-149-5p in PML progression/persistence and suggest this axis as a potential therapeutic target for PML immunomodulation.
2025-12-10 | GSE313144 | GEO
Project description:Bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma, have distinct molecular subtypes. The proliferative subtype, enriched with bronchial dysplasia, had decreased expression of an antigen processing/presentation gene co-expression module in progressive/persistent versus regressive PMLs, suggesting a functional impact of these genes on immune evasion. Here, we performed miRNA sequencing, miRNA in situ hybridization (ISH), and spatial proteomics of bronchial biopsies from patients at high risk for lung cancer. A miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of the antigen presentation gene module. Staining on adjacent biopsy tissue showed that hsa-miR-149-5p was predominantly expressed in the epithelium and up-regulated in progressive/persistent proliferative lesions. Targets of this miRNA, the transcriptional coactivator of MHC-I gene expression, NLRC5, and the genes it regulates were down-regulated in these lesions. Decreased NLRC5 expression reduced both IFN-gamma induced MHC-I surface expression and CD8 T cell cytotoxicity in lung squamous cancer cells. In PMLs, basal cells with high levels of NLRC5 were in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in vivo. These findings indicate a functional role for hsa-miR-149-5p in PML progression/persistence and suggest this axis as a potential therapeutic target for PML immunomodulation.
2025-12-10 | GSE313145 | 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:Airway epithelial cells obtained via bronchoscopy from high risk subjects with and without bronchial premalignant lesions
| PRJNA315447 | ENA
Project description:Up-regulation of an epithelial miRNA is associated with immune evasion in progressive bronchial premalignant lesions.
| PRJNA1378690 | ENA
Project description:While lung cancer is the leading cause of cancer death in the US, we have a limited understanding of the earliest molecular events preceding the onset of disease. Prior work has demonstrated that cigarette smoke creates a molecular “field of injury” throughout the airway epithelium and that there are distinct alterations in the airway transcriptome among smokers who have lung cancer. Molecular characterization of this airway “field of injury” in current and former smokers with premalignant lesions (PMLs) could provide novel insights into the earliest molecular events associated with lung carcinogenesis and identify relatively accessible biomarkers to guide lung cancer detection and early intervention. Using mRNA sequencing (mRNA-Seq), we profiled 82 cytologically normal bronchial airway epithelial cells collected during autofluorescence bronchoscopy from high-risk smokers with and without bronchial PMLs, 75 of which were used in downstream analyses. We identified 280 genes differentially expressed in the “field of injury” between subjects with (n=50) and without (n=25) PMLs (FDR<0.002), 81 of which were up-regulated in subjects with PMLs. Oxidative phosphorylation (OXPHOS), the electron transport chain (ETC), and mitochondrial protein transport pathways were strongly enriched among these up-regulated genes (FDR<0.05). We next demonstrated that OXPHOS activation is shared between the “field” and the PMLs with increased oxygen consumption and increased staining for mitochondrial markers in biopsies of PMLs from patients as well as an animal model of lung squamous cell carcinoma (SCC) premalignancy. The 280-gene signature also has a significant concordant relationship to gene expression changes identified in PMLs adjacent to lung SCC tumors, in lung SCC tumors, and in the cytologically normal airway of individuals with lung cancer (FDR<0.05). These findings suggest that these expression changes are reflective of early cancer-associated changes occurring throughout the respiratory tract, and that pathways such as OXPHOS may be targets for chemoprevention. We subsequently developed an airway gene expression biomarker that predicts the presence of PMLs (AUC=0.92, n=17 samples in test set) and show that changes in the biomarker score are associated with progression and regression of PMLs in an independent cohort (AUC=0.75, n=51 samples). The biomarker results indicate that molecular alterations in the field of injury are dynamic with progression or regression of PMLs, suggesting that these changes may be leveraged to stratify high-risk smokers with progressive disease into early intervention trials and monitor disease progression or recurrence.
2017-05-25 | GSE79209 | GEO