Characterizing senescent lung epithelial cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA699009 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13615000.fastq.gz | Fastqsanger.gz | |||
| SRR13615001.fastq.gz | Fastqsanger.gz | |||
| SRR13615002.fastq.gz | Fastqsanger.gz | |||
| SRR13615003.fastq.gz | Fastqsanger.gz | |||
| SRR13615004.fastq.gz | Fastqsanger.gz |
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Project description:Recent publications have implicated senescent alveolar epithelial cells as the cause of lung remodeling and fibrosis. We sought to better understand the heterogeneity in the basal epithelial cell population, especially with regards to characterizing senescent alveolar epithelial cells. The basal cell cultures contain a portion of cells that display a senescent phenotype and stain for a marker of senescence. We also sought to understanding the heterogeneity in the fibroblast population. Primary fibroblast cultures stained with myofibroblast markers show that only a portion of the cells are positive for ACTA2, suggesting that there are at least two distinct populations in this particular cell type. The diversity in this cell type remains uncharacterized at this point.
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Project description:Accumulation of senescent cells in the tumour microenvironment can drive tumourigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumours. Single cell transcriptomics identify a population of tumour-associated macrophages, expressing a unique array of pro-tumourigenic SASP factors and surface proteins, that are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, and macrophage depletion, result in a significant reduction in tumour burden and increased mouse survival of KRAS-driven lung cancer models. Of translational relevance, we reveal the presence of macrophages with senescent features in human lung premalignant lesions, but not in adenocarcinomas. Together, our results have uncovered a population of senescent macrophages contributing to the initiation and progression of lung cancer, thus opening potential therapeutic avenues and cancer preventative strategies.
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Project description:Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. Current treatments are insufficient in improving the prognosis of lung cancer patients with comorbid idiopathic pulmonary fibrosis (IPF-LC). Senescent fibroblasts play a pivotal role within the tumor microenvironment, influencing tumor progression by secreted exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we sought to investigate the impact of senescent IPF lung fibroblast-derived exosomes on non-small cell lung cancer (NSCLC). Our results show that IPF fibroblasts (diseased human lung fibroblasts, DHLF) express significant senescence markers, promoting NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, we observed senescent DHLFs secret more exosomes (DHLF-exosomes), which could enhance proliferation and colony-forming ability of cancer cells. Proteomic analysis of DHLF-exosomes identified upregulation of SASP factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-exosomes in vivo and in vitro. Mechanistically, MMP1 acted via activating the PI3K-AKT-mTOR pathway. In conclusion, our results suggest that exosomal MMP1 derived from senescent IPF fibroblasts promotes NSCLC proliferation and colony formation by targeting PAR1 and activating the PI3K-AKT-mTOR pathway. These findings provide a novel therapeutic approach for patients with IPF-LC.
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