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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE168038 | GEO | 2022/12/15

REPOSITORIES: GEO

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

Project description: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.

2022-12-15 | GSE198439 | 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.

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Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (2)

Project description:In this study we examine the outcomes of p16INK4a activation in the adult epidermis. We found that prolonged expression of p16INK4a induces epidermal hyperplasia and dysplasia. We also found that continued p16INK4a expression increased the number of epidermal papillomas that developed after carcinogen treatment. Profling of p16INK4a- expressing cells showed elevated levels of Wnt-pathway ligands and targets, and pharmacologic or genetic Wnt inhibition suppressed p16-induced hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16-expressing cells are typically found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that in addition to its cell-autonomous role in blocking cell proliferation, p16 can induce hyperplasia through paracrine stimulation, suggesting that its activity contributes to the formation of early premalignant epidermal lesions.

2020-04-06 | GSE146978 | GEO

Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (1)

2020-04-06 | GSE121728 | GEO

Feedback Circuit among INK4 Tumor Suppressors Constrains Human Glioblastoma Development

Project description:We have developed a nonheuristic genome topography scan (GTS) algorithm to characterize the patterns of genomic alterations in human glioblastoma (GBM), identifying frequent p18INK4C and p16INK4A codeletion. Functional reconstitution of p18INK4C in GBM cells null for both p16INK4A and p18INK4C resulted in impaired cell-cycle progression and tumorigenic potential. Conversely, RNAi-mediated depletion of p18INK4C in p16INK4A-deficient primary astrocytes or established GBM cells enhanced tumorigenicity in vitro and in vivo. Furthermore, acute suppression of p16INK4A in primary astrocytes induced a concomitant increase in p18INK4C. Together, these findings uncover a feedback regulatory circuit in the astrocytic lineage and demonstrate a bona fide tumor suppressor role for p18INK4C in human GBM wherein it functions cooperatively with other INK4 family members to constrain inappropriate proliferation. Keywords: SuperSeries DNA copy number and mRNA transcriptome of human glioblastoma tumors were profiled using Agilent and Affymetrix microarrays. This SuperSeries is composed of the following subset Series: GSE7602: Human GBM tumor vs Normal Human DNA GSE9171: Expression data from human GBM tumors and cell lines GSE9177: Human GBM tumor vs Normal Human DNA

2008-04-29 | E-GEOD-9200 | 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

Low dose chronic angiotensin II induces selective senescence of kidney endothelial cells

Project description:Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a mouse model that mimics the initiation of hypertension. We utilized the INK-ATTAC (p16ink4a - Apoptosis Through Targeted Activation of Caspase 8) mouse model that allows for conditional elimination of p16ink4a -dependent senescent cells by administration of AP20187. INK-ATTAC mice received continuous low doses of angiotensin II over 3 weeks and AP20187 vs vehicle. In the kidneys increased expression of ATM, p15 and p21 matched with angiotensin II induction of senescence-associated secretory phenotype genes MMP3, FGF2, IGFBP2, and tPA. AP20187-mediated elimination of p16-dependent senescent cells prevented physiologic, cellular and molecular responses to angiotensin II. We conclude that angiotensin II induces a relatively selective senescence transformation of renal endothelial cells that could provide a novel therapeutic target for senolytic drugs as alternative treatment options for hypertension and resulting tissue damage.

2022-01-10 | GSE179195 | GEO

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