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Airway Basal Cells of Healthy Smokers Express an Embryonic Stem Cell Signature Relevant to Lung Cancer

ABSTRACT: Activation of the human embryonic stem cell (hESC)-signature genes has been observed in various epithelial cancers. In this study, we found that the hESC signature is selectively induced in the airway basal stem/progenitor cell population of healthy smokers (BC-S), with a pat-tern similar to that activated in all major types of human lung cancer. We further identified a subset of 6 BC-S hESC genes, whose coherent overexpression in lung AdCa was associated with reduced lung function, poorer differentiation grade, more advanced tumor stage, remarkably shorter survival and higher frequency of TP53 mutations. BC-S shared with hESC and a consid-erable subset of lung carcinomas a common TP53 inactivation molecular pattern which strongly correlated with the BC-S hESC gene expression. These data provide transcriptome-based evi-dence that smoking-induced reprogramming of airway BC towards the hESC-like phenotype might represent a common early molecular event in the development of aggressive lung carci-nomas in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19722 | GEO | 2014/09/09

SECONDARY ACCESSION(S): PRJNA121921

REPOSITORIES: GEO

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Airway Basal Cells of Healthy Smokers Express an Embryonic Stem Cell Signature Relevant to Lung Cancer

Project description:Activation of the human embryonic stem cell (hESC)-signature genes has been observed in various epithelial cancers. In this study, we found that the hESC signature is selectively induced in the airway basal stem/progenitor cell population of healthy smokers (BC-S), with a pat-tern similar to that activated in all major types of human lung cancer. We further identified a subset of 6 BC-S hESC genes, whose coherent overexpression in lung AdCa was associated with reduced lung function, poorer differentiation grade, more advanced tumor stage, remarkably shorter survival and higher frequency of TP53 mutations. BC-S shared with hESC and a consid-erable subset of lung carcinomas a common TP53 inactivation molecular pattern which strongly correlated with the BC-S hESC gene expression. These data provide transcriptome-based evi-dence that smoking-induced reprogramming of airway BC towards the hESC-like phenotype might represent a common early molecular event in the development of aggressive lung carci-nomas in humans. Affymetrix arrays were used to assess gene expression data of genes realted to human embryonic stem cells in large airway epithelium obtained by fiberoptic bronchoscopy of 21 healthy non-smokers and 31 healthy smokers, basal cell culture of large airway epithelium obtained by fiberoptic bronchoscopy of 4 healthy nonsmokers and 4 healthy smokers and cells obtained from tumor tissues of 4 individuals.

2014-09-09 | E-GEOD-19722 | biostudies-arrayexpress

Gene expression profiling of normal lung tissue adjacent to lung adenocarcinoma (ADCA)

Project description:Individual variations in the transcriptional profile of normal lung tissue may reflect the lung ADCA patients’ predisposition to a specific clinical stage Associations between clinical outcome of cancer patients and the gene expression signature in primary tumors at time of diagnosis have been reported. To test whether gene expression patterns in the normal tissue surrounding the cancerous tissue might correlate with clinical stage, we compared transcriptome of normal lung samples of adenocarcinoma (ADCA) smoker patients of clinical stage I versus stage >I, and identified 55 differentially expressed genes. Eight out of 10 genes validated by quantitative real-time PCR confirmed statistical association with clinical stage, with 6 genes downregulated in high clinical stage patients, including the TMEM100 gene showing the best statistical association. Five of these 6 genes were also downregulated in lung ADCA tissue as compared to normal tissue. Functional studies in vitro indicated that four of them (SLC14A1, SMAD6, TMEM100, and TXNIP) inhibited colony formation when over-expressed by transfection in lung cancer cell lines, suggesting their potential tumor-suppressor activity. Our findings indicated that individual variations in the transcriptional profile of normal lung tissue may reflect the lung ADCA patients’ predisposition to a specific clinical stage.

2013-01-01 | GSE31267 | GEO

Gene expression profiling of normal lung tissue adjacent to lung adenocarcinoma (ADCA)

2013-01-01 | E-GEOD-31267 | biostudies-arrayexpress

Smoking Dysregulates the Human Airway Basal Cell Transcriptome at COPD-linked Risk Locus 19q13.2

Project description:Rationale: Genome-wide association studies (GWAS) and candidate gene studies have identified a number of loci linked to susceptibility of chronic obstructive pulmonary disease (COPD), a smoking-related disorder that originates in the airway epithelium. Objectives: Since airway basal cell (BC) stem/progenitor cells exhibit the earliest abnormalities associated with smoking (hyperplasia, squamous metaplasia), we hypothesized that smoker BC have a dysregulated transcriptome linked, in part, to known GWAS/candidate gene loci. Methods: Massive parallel RNA sequencing was used to compare the transcriptome of BC purified from the airway epithelium of healthy nonsmokers (n=10) and smokers (n=7). The chromosomal location of the differentially expressed genes was compared to loci identified by GWAS and candidate gene studies to confer risk for COPD. Measurements and Main Results: Smoker BC have 676 known genes differentially expressed compared to nonsmoker BC, dominated by smoking up-regulation. Strikingly, 166 (25%) of these genes are located on chromosome 19, with 13 localized to 19q13.2 (p<10-4 compared to chance), including TGFB1, LTBP4, EGLN2 and NFKBIB, genes associated with risk for COPD. Conclusions: These observations provide the first direct link of known genetic risks for smoking-related lung disease with the specific population of lung cells that undergoes the earliest changes associated with smoking. The human airway basal cell transcriptome of 7 smokers versus 10 nonsmokers was compared using massive parallel RNA sequencing (Illumina HiSeq 2000).

2014-05-08 | E-GEOD-47718 | biostudies-arrayexpress

Smoking Dysregulates the Human Airway Basal Cell Transcriptome at COPD-linked Risk Locus 19q13.2

2014-05-08 | GSE47718 | GEO

Distal-to-Proximal Re-patterning of Small Airway Epithelium in Smoking-associated Chronic Obstructive Pulmonary Disease

Project description:The proximal-distal patterning program determines unique structural and functional properties of proximal and distal airways in the adult lung. Based on the knowledge that remod-eling of distal airways is the major pathologic feature of chronic obstructive pulmonary disease (COPD), and that small airway epithelium (SAE), which covers distal airways, is the primary site of the initial smoking-induced changes relevant to COPD pathogenesis, we hypothesized that in COPD smokers, the SAE transcriptome loses its region-specific biologic identity and takes on the transcriptional pattern of the proximal airways. By analyzing human airway epithelium col-lected by bronchoscopic brushings from proximal and distal airways of healthy smokers, proxi-mal and distal airway epithelial transcriptome signatures were identified. Dramatic smoking-dependent suppression of distal signature paralleled by acquisition of the proximal airway epithe-lial phenotype was found in the SAE of COPD smokers. Distal-proximal re-patterning observed in the SAE of smokers in vivo was reproduced in vitro by stimulating SAE basal cells (BC), the stem/progenitor cells of the SAE, with EGF, a growth factor up-regulated in airway epithelium by smoking. Together, this study identifies distal-proximal SAE re-patterning as a characteristic feature of small airway disordering in COPD smokers potentially driven by EGF/EGFR-mediated reprogramming of SAE BC stem/progenitor cells.

2017-07-18 | GSE64614 | GEO

Transcriptome determinants of lung seeding by mammary tumor cells

Project description:Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine; that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.

2018-01-01 | GSE104264 | GEO

Activation of Notch1 and Notch3 Skews Human Airway Basal Cell Differentiation Toward a Secretory Pathway

Project description:Airway basal cells (BC) function as progenitor cells capable of differentiating into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. The objective of this study was to define the role of Notch signaling in regulating human airway BC differentiation into a pseudostratified mucociliated epithelium. Notch inhibition with γ-secretase inhibitors demonstrated Notch activation is essential for BC differentiation into secre-tory cells and ciliated cells, but more so for the secretory lineage. Sustained Notch activation via lentivirus expression of the intracellular domain of each Notch receptor (NICD1-4) demonstrated that the Notch 2 and 4 pathways have little effect on BC differentiation, while activation of the Notch1 or 3 pathways has a major influence, with persistent expression of NICD1 or 3 resulting in a skewing toward secretory cell differentiation with a parallel decrease in ciliated cell differentiation. These observations provide insights into the control of the balance of BC differentiation into the secretory vs ciliated cell lineage, a balance that is critical for maintaining the normal function of the airway epithelium in barrier defense against the inhaled environment. Array-based expression profiling of the Notch signaling pathway genes specifically in human airway basal cells.

2015-04-13 | E-GEOD-53537 | biostudies-arrayexpress

Endothelial MMP14 is required for endothelial dependant growth support of human airway basal cells

Project description:Human airway basal cells (BC) are the stem/progenitor population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of BC allows for potential paracrine signaling between BC and the underlying non-epithelial stromal cells. In support of this, we previously demonstrated endothelial cells (EC) support growth of BC during co-culture via vascular endothelial growth factor A (VEGFA)-mediated signaling. Building on these findings, RNA sequencing analysis demonstrated that BC express multiple fibroblast growth factor (FGF) ligands (FGF2, 5, 11 and 13) with only FGF2 and FGF5 capable of functioning in a paracrine manner to mediate FGFR1 signaling. Antibody mediated blocking of FGFR1 during BC-EC co-culture significantly reduced EC dependent BC growth. Stimulation of EC via BC-derived growth factors resulted in EC expression of matrix metallopeptidase 14 (MMP14) and shRNA mediated knockdown of EC MMP14 significantly reduced EC dependent growth of BC. Overall, these data characterize a novel growth factor mediated reciprocal “cross-talk” between human airway BC and EC that regulates proliferation of BC.

2024-06-05 | GSE64461 | GEO

Transcription profiling by array of human non-small cell lung cancer and normal adjacent lung tissue matched pairs

Project description:Affymetrix exon array data set (HuEx-1.0_st) derived from matched pairs of non-small cell lung cancer (NSCLC) and normal adjacent lung tissue (NAT). This data set includes both the adenocarcinoma (AdCa) as well as the squamous cell carcinoma (SCC) subtype of NSCLC.

2011-03-01 | E-MEXP-2644 | biostudies-arrayexpress

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