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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE168037 | 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 [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

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

Nintedanib induces senolytic effect via STAT3 inhibition

Project description:Selective removal of senescent cells, or the concept of senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced cell death in primary human diploid fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without cytotoxicity. Interestingly, compared with ABT263, nintedanib showed a different mode of activating caspase-9 in the intrinsic apoptotic pathway, in that nintedanib did not suppress the levels of Bcl-2 family proteins in senescent cells. In more detail, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused drug-induced cell death in senescent cells. STAT3 knockdown in senescent cells also induced caspase activation. Moreover, nintedanib reduced the number of senescent cells stained based on senescence-associated β-galactosidase activity and airway resistance in a mouse model of bleomycin-induced lung fibrosis. Overall, we identified that nintedanib could be used as a new senolytic agent and that inhibiting STAT3 could be a potential approach for inducing selective cell death in senescent cells. Our findings will pave the way for expanding senolytic toolkits in response to various aging statuses and age-related diseases.

2022-09-06 | GSE210020 | GEO

Senescent cell elimination modifies features of Alzheimer’s disease in 3xTg-AD mice

Project description:Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Here, we show that treatment with senolytics (ABT263 (navitoclax) or a combination of dasatinib and quercetin (D+Q)) or transgenic removal of p16-expressing cells (via INK-ATTAC) reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation was attenuated with senescent cell removal. Unfortunately, these beneficial effects were not seen with short-term senolytic treatment in mice with more advanced disease. Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for treatment of this debilitating disease.

2024-03-20 | GSE231332 | 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

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

Senescent cells suppress innate vascular smooth muscle cell repair functions

Project description:Treatment of LDLr-/- mice with the senolytic ABT263 enhances VSMC phenotypic switching to promote formation, maintenance, and restoration of the fibrous cap in atherosclerotic lesions of all stages.

2021-05-11 | GSE130382 | GEO

Acceleration of beta cell aging plays a key role in diabetes and senolysis improves metabolic, functional and cellular outcomes

Project description:The risk of type 2 diabetes increases with age. Although changes in function and proliferation of aged beta cells resemble those preceding the development of diabetes, the contribution of beta cell aging and senescence remains unclear. The proportion of aged beta cells increases with animal age but even in young mice, senescent beta cells can be found. We showed that different models of insulin resistance accelerated aging and senescence marker expression in beta cells, BGal, led to loss of function and impaired glucose tolerance. Clearance of p16Ink4a+ cells, using the INK-ATTAC mouse model, ameliorated glucose metabolism, insulin secretion and decreased expression of aging, senescence and SASP genes in pancreatic islets. Senolytic drug ABT263 also improved glucose metabolism and beta cell identity when administered during insulin resistance. Human beta cells from diabetic and non-diabetic donors shared some of the same biology laying the foundation for translation into humans. These novel findings lay the framework to pursue senolysis of beta cells as a preventive and alleviating strategy for T2D.

2019-05-10 | GSE121539 | 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

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