Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
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PROVIDER: PRJNA957291 | ENA |
REPOSITORIES: ENA
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Project description:Clearance of a senescent macrophage-enriched niche ameliorates tumorigenesis in KRAS-driven murine lung cancer models
| PRJNA840887 | ENA
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.
2023-06-02 | GSE230054 | GEO
Project description:Understanding the important role of the tumour microenvironment on tumour initiation and progression is vital for a comprehensive understanding of cancer biology to design effective treatment strategies. Cellular senescence, while traditionally thought of as a cell autonomous tumour-suppressive response to potentially oncogenic insults, is now appreciated to have paracrine tumour promoting roles. We demonstrate a pro-tumourigenic effect of senescent microenvironmental cells on mouse lung tumour progression. To better understand the characteristics of these pro-tumourigenic senescent cells in the tumour microenvironment, we compare putatively senescent cells (reported by mCherry-expression) and non-senescent cells (mCherry-negative cells) from the lung microenvironment of mice induced to form lung tumours by oncogenic KrasG12D-expression in the lung epithelium. Putatively senescent cells are isolated by FACS, based on mCherry-expression which is expressed under the control of the Cdkn2a (p16) locus using a novel genetically engineered allele (p16FDR/+), along with their non-senescent counterparts for comparison by single cell RNA-sequencing.
2023-06-14 | GSE203447 | GEO
Project description:Cellular senescence is a central barrier to tumorigenesis, acting to block the proliferation of premalignant cells. However, senescent cells residing within tumor lesions can also exert paracrine effects influencing tumor growth and progression. Premalignant pancreatic intraepithelial neoplasia (PanIN) lesions contain senescent cells, yet whether these influence disease progression is unknown. Here we report that senescent cells in PanINs that develop in a Kras-driven mouse model express a pro-inflammatory gene signature, which includes high Cox2 levels. Pharmacologic Cox2 inhibition caused a dramatic reduction in PanIN growth. Senolytic treatment with the Bcl2-family inhibitor ABT-737 reduced the numbers of Cox2-expressing PanIN cells and blocked PanIN formation and progression to carcinoma. These findings indicate that senescent PanIN cells support tumor growth and progression through Cox2 activity, representing crosstalk between interspersed senescent and dividing premalignant cells. Targeted elimination of senescent cells may thus be effective in limiting progression of precancerous lesions.
2021-02-17 | GSE128319 | GEO
Project description:Non-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCe, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCe expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCe-deficient, conditionally activatable allele of oncogenic Kras (LSL-Kras G12D ;PKCe -/- mice) we were able to demonstrate the requirement of PKCe for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCe-deficient KRAS-dependent NSCLC cells. Moreover, PKCe-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCe and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCe in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCe for lung cancer therapeutics.
2020-07-31 | GSE149205 | GEO
Project description:KRAS induces lung tumorigenesis through microRNAs modulation
| PRJNA433453 | ENA
Project description:Clearance of p21-highly-expressing senescent cells accelerates wound healing
| PRJNA1168086 | ENA
Project description:Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a-positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions’ being a potential therapeutic avenue for alleviating age-associated cognitive impairment.
2021-02-06 | GSE161340 | GEO
Project description:Clearance of p21-highly-expressing senescent cells accelerates cutaneous wound healing
| PRJNA1167732 | ENA
Project description:REQUIREMENT FOR PKC EPSILON IN KRAS-DRIVEN LUNG TUMORIGENESIS
| PRJNA627658 | ENA