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Clearance of a senescent macrophage-enriched niche ameliorates tumorigenesis in KRAS-driven murine lung cancer models

ABSTRACT: Clearance of a senescent macrophage-enriched niche ameliorates tumorigenesis in KRAS-driven murine lung cancer models

PROVIDER: PRJNA840887 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19332476.fastq.gz	Fastqsanger.gz
	SRR19332477.fastq.gz	Fastqsanger.gz
	SRR19332478.fastq.gz	Fastqsanger.gz

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Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

Project description:Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

| PRJNA957291 | ENA

Clearance of a senescent macrophage-enriched niche ameliorates tumorigenesis in KRAS-driven murine lung cancer models

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

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

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

Clearance of p21-highly-expressing senescent cells accelerates wound healing

Project description:Clearance of p21-highly-expressing senescent cells accelerates wound healing

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Transcriptome of senescent and non-senescent cells within PanIN pancreatic premalignant lesions in a KRas-driven mouse model

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

Whole-Body Senescent Cell Clearance Alleviates Age-Related Brain Inflammation and Cognitive Impairment in Mice

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

Clearance of p21-highly-expressing senescent cells accelerates cutaneous wound healing

Project description:Clearance of p21-highly-expressing senescent cells accelerates cutaneous wound healing

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Targeting senescent hepatocytes using the THBD-PAR1 inhibitor Vorapaxar ameliorates NAFLD progression.

Project description:Targeting senescent hepatocytes using the THBD-PAR1 inhibitor Vorapaxar ameliorates NAFLD progression.

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Transcriptome of senescent and non-senescent cells within PanIN pancreatic premalignant lesions in a KRas-driven mouse model

Project description:Transcriptome of senescent and non-senescent cells within PanIN pancreatic premalignant lesions in a KRas-driven mouse model

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Clearance of p21-highly-expressing senescent cells accelerates wound healing

Project description:Targeting senescent cells for therapeutic purposes is gaining momentum across various organ systems. However, concerns about potential off-target effects have been raised. Previous studies have shown that removing senescent cells expressing high levels of p16 (p16high) can hinder processes like wound healing. Here, we identify a distinct senescent cell population during dermal wound healing characterized by high expression level of p21 (p21high) using the p21-Cre mouse model. Using a standard cutaneous injury model, we find that eliminating p21high cells can expedite wound closure, in contrast to the effects of removing p16high cells. Through Xenium, a single cell spatial imaging platform, we show that p21high cells are distinct from p16high cells, with p21high cells mainly comprising fibroblasts, immune cells, keratinocytes, and endothelial cells with a pro-inflammatory profile. Moreover, inhibition of NF-kB signaling specifically from p21high cells partially contributes to the accelerated wound healing rates. These findings highlight the heterogeneity of senescent cells during wound healing responses within the skin and likely in other conditions.

2024-10-07 | GSE278611 | GEO

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