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Cellular senescence in malignant cells promotes tumorigenesis in mouse and patient glioblastoma [p16]

ABSTRACT: The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs and characterize their action on the tumor microenvironment at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared p16-3MR+GCV to WT+GCV control GBMs that were harvested 7 days after the last GCV injection.

ORGANISM(S): Mus musculus

PROVIDER: GSE198439 | GEO | 2022/12/15

REPOSITORIES: GEO

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Cellular senescence in malignant cells promotes tumorigenesis in mouse and patient glioblastoma [10X scRNA-seq]

Project description:The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs, at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared two p16-3MR+GCV to two WT+GCV control GBMs that were harvested 7 days after the last GCV injection. p16Ink4a Hi senescent cells were a subset of malignant cells, mostly grouped in the astrocyte cluster and to a lesser extend in the NP-like cluster. We also found that p16Ink4a Hi senescent cells deletion modifies the cell state of malignant cells and modulates the tumor microenvironment. This study allowed us to define a GBM senescence signature.

2022-12-15 | GSE168038 | GEO

Cellular senescence in malignant cells promotes tumorigenesis in mouse and patient glioblastoma [bulk RNA-seq]

Project description:GBM mouse model: The goal of this study is to compare the transcriptomic landscape at the endpoint of GBMs upon senescent cells deletion. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) upon ganciclovir (GCV) injection. We compared p16-3MR+GCV GBMs to two control conditions, either WT+GCV or p16-3MR+GCV. We showed a slight decreased of p16Ink4a transcripts in p16-3MR+GCV compared to WT+GCV GBMs and GSEA demonstrated significant down-regulation of senescence pathways in p16-3MR+GCV GBMs compared to control GBMs. GBM-derived organoids: We used a mouse GBM-derived organoids model to further explore the function of Nrf2, that we identified as one potential trigger of the pro-tumoral action of p16Ink4a Hi malignant cells. We compared GBM-derived organoids treated with the senolytic ABT263 (Navitoclax; inhibitor of the anti-apoptotic proteins Blcl2 and BCL-xL) or vehicle (vhc) after 14 days in culture. We validated ABT263 efficacy via the significant downregulation of the expression of p16Ink4a, p15Ink4b and p21Cip1 senescent markers. We further identified upon senolytic treatment, downregulated genes encoding for SASP. Importantly, GSEA revealed a significant downregulation of Nrf2 pathway upon senolytic treatment.

2022-12-15 | GSE168037 | GEO

Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension

Project description:Experimental ocular hypertension (IOP) induces senescence of retinal ganglion cells (RGCs) that mimicks events occurring in human glaucoma. An established transgenic p16-3MR mouse model in which the systemic administration of the small molecule ganciclovir (GCV) selectively kills p16INK4a-expressing cells was used to compare transcriptomes of retinas from IOP and control eyes in GCV-treated and non-treated mice, to investigate how experimental removal of senescent p16INK4a-positive cells impacts retinal cells in conditions resembling glaucoma.

2020-12-01 | GSE141725 | GEO

P16 positive microglia population identified in the aged mouse brain

Project description:Senescent cells are in a state of permanent cell cycle arrest, which is mediated by the Cyclin Dependent Kinase (CDK)4/6 inhibitor p16. During ageing, p16-expressing (P16pos) cells accumulate in tissues and promote multiple age-related pathologies, including neurodegenerative diseases. We evaluated the accumulation and the phenotype of senescent cells in the aged brain with a transgenic reporter mouse (p16-3MR), which allows for isolation of P16poscells. First, we showed that the number of P16pos cells is significantly increased in old brains. Second, using bulk RNAseq, we demonstrated that P16pos cells express high levels of inflammatory and lysosomal genes. Third, using single-cell RNAseq, we identified P16pos brain cells as being primarily microglia. Interestingly, the transcriptional profile of P16pos microglia cells is distinct from cell type signatures associated with senescence or defined microglia populations. Taken together, our study provides evidence for the accumulation of a novel P16pos microglia population in the aging brain, which could result in loss of tissue homeostasis and contribute to brain dysfunction.

2021-10-14 | GSE151459 | GEO

Gene expression profile of p16-induced senescence in normal human diploid fibroblasts.

Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells. TIG-3 ER-p16 cells (primary normal human diploid fibroblasts expressing a 4-hydroxytamoxifen(4-OHT) regulatable form of human p16) were cultured for 7 days with or without 4-OHT. Total RNA was isolated using TRIzol reagent and were analyzed using the hum

2014-04-10 | E-GEOD-49863 | biostudies-arrayexpress

Expression data from RCAS PDGFB/Nestin tv-A glioma cells within Ptprd+/+p16-/- (n=2), Ptprd+/-p16-/- (n=2), and Ptrpd-/-p16-/- (n=3) mice.

Project description:PTPRD is a tumor suppressor of glioma that is frequently co-deleted with CDKN2A/p16. We show that Ptprd and p16 cooperate to promote gliomagenesis in the RCAS PDGFB / Nestin tv-A glioma mouse model. We found unique gene expression changes within tumor cells of Ptprd+/-p16-/- vs. Ptprd+/+p16-/- and Ptprd-/-p16-/- tumor cells. Neonatal mice were injected with RCAS PDGFB GFP. At symptoms, or at 12 weeks post injection, GFP+DAPI- tumor cells were sorted for RNA extraction and hybridization on Affymetrix microarrays. The mouse strain used was a mixed background of C57/BL6 and FVB/N. Ptprd mice were from Uetani et al. 2000 and p16/Nestin-tvA mice were from Tchouganouva et al. 2007.

2014-06-02 | E-GEOD-55061 | biostudies-arrayexpress

p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells [RNA-seq: Lung Epithelial Cells]

Project description:The accumulation of senescent cells promotes aging, but a molecular mechanism that senescent cells use to evade immune clearance and accumulate remains to be elucidated. Here, we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to the elimination of p16, PD-L1-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of PD-L1 as a target for treating senescence-mediated age-associated diseases.

2024-02-14 | GSE225286 | GEO

p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells [RNA-seq: Lung Alveolar Macrophages]

2024-02-14 | GSE225285 | GEO

Gene expression profile of p16-induced senescence in normal human diploid fibroblasts.

Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells.

2014-04-10 | GSE49863 | GEO

Effect of p16 deficiency on gene expression in primary hepatocytes

Project description:*Objectives:* In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Genome wide association studies identified SNPs near the cell cycle regulator CDKN2A/p16INK4a (p16) as strongly associated with risk of developing type 2 diabetes (T2D). T2D is associated with numerous perturbations of hepatic lipid and glucose metabolism. We have recently shown that p16 controls fasting-induced hepatic gluconeogenesis in mice. However, whether p16 may also affect hepatic lipid homeostasis is unknown. *Results:* In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism and enhanced activation of PPAR. This led to increased mitochondrial fatty acid oxidation (FAO) through a mechanism requiring the catalytic AMPK 2 subunit and SIRT1. By contrast, *p16* overexpression was associated with triglyceride accumulation and increased lipid droplet numbers *in vitro*, and decreased ketogenesis and hepatic mitochondrial activity *in vivo*. Gene expression analysis of human liver samples revealed a negative correlation between *CDKN2A* expression and *PPARA* and its target genes, suggesting a potential association between hepatic p16 expression and FAO in obese humans. *Conclusions:* Our findings demonstrate that p16 plays a key role in hepatic lipid metabolism and may thus contribute to the development of metabolic diseases.

2020-10-09 | GSE134625 | GEO

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