Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance
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ABSTRACT:
PROVIDER: PRJNA801491 | ENA |
REPOSITORIES: ENA
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Project description:Cellular senescence is a homeostatic program associated with tumor suppression, wound healing, and certain age related pathologies. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while at the same time activate an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell-mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.
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Project description:Cellular senescence is a homeostatic program associated with tumor suppression, wound healing, and certain age related pathologies. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while at the same time activate an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell-mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.
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Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. The levels of senescence marker, p16INK4A and senescence-associated β-galactosidase (SA-β-gal) activity are higher in PA endothelial cells (ECs) isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16fl/fl-Cdh5(PAC)-CreERT2 (p16iΔEC) mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing platelet-derived growth factor (PDGFB) expression. Transcriptomic analyses of IPAH patient or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and their interaction with TWIST1. Knockdown of p16INK4A attenuates the expression of PDGFB and TWIST1 in IPAH patient PAECs or hypoxia-treated mouse lungs and suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel implanted on the mouse lungs. Hypoxia-treated mouse lung EC-derived exosomes stimulate DNA synthesis and migration of PASMCs in vitro and in the gel implanted on the mouse lungs, while p16iΔEC mouse lung EC-derived exosomes inhibit the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.
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Project description:Therapeutic drugs are commonly used for treatment various cancers. However, despite to this purpose, Cancer treated by drugs undergoes senescence phenotypes and is known to acquire more aggressive ability. Futhermore, senescence can be induced vairous type of drug via differential mechanisms. Therefore, we analyzed to validate differential charateristics of senescence phenotypes compare between drugs.
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Project description:Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor Natural Killer (NK) and T cell immunity. Here we found the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated epigenetic repression of pro-inflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in PDAC patients. These results demonstrate that EZH2 represses of the pro-inflammatory SASP, and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.
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2012-08-28 | E-GEOD-40403 | biostudies-arrayexpress
Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the non-muscularized distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. Here, we have demonstrated that endothelial senescence mediates PH pathology by increasing platelet-derived growth factor (PDGFB) expression. The levels of senescence markers p16INK4A and senescence-associated β-galactosidase (SA-β-gal) are higher in PA endothelial cells (ECs) isolated from IPAH patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16INK4Afl/fl-Cdh5(PAC)-CreERT2 mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing PDGFB expression. Transcriptomic analyses of idiopathic pulmonary arterial hypertension (IPAH) patient lung ECs or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and interaction with TWIST1. Increases in the levels of PDGFB and TWIST1 in hypoxia-treated mouse lung ECs or IPAH patient lung ECs are attenuated by knocking down p16INK4A expression or treating with senolytic reagents. Knockdown of p16INK4A also suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel. Exosomes collected from hypoxia-treated mouse lung ECs stimulate SMC DNA synthesis and migration in vitro and in the gel implanted on the mouse lungs, while p16INK4A knockdown in ECs inhibits the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.
2022-10-12 | GSE193272 | GEO
Project description:Endothelial cell senescence is one of the most important causes of vascular dysfunction and atherosclerosis. Circular RNAs (circRNAs) are endogenous RNA molecules with covalently closed-loop structures, which have been reported to be abnormally expressed in many human diseases. However, the potential role of circRNAs in endothelial cell senescence remains unknown. Here, we compared the expression patterns of circRNAs in young and senescent human endothelial cells using RNA sequencing. Among the differentially expressed endothelial cell senescence-associated circRNAs, we identified circGNAQ, generated by circularization of exons 4 and 5 of the GNAQ gene, as a circRNA showing markedly reduced levels in senescent endothelial cells. CircGNAQ silencing in young endothelial cells triggered senescence, as determined by a rise in senescence-associated β-galactosidase activity, reduced cell proliferation, and suppressed angiogenesis; circGNAQ overexpression showed the opposite effects. Mechanistic studies revealed that circGNAQ acted as an endogenous miR-146a-5p sponge to sequester and inhibit miR-146a-5p activity, leading to increased PLK2 expression. In vivo studies showed that circGNAQ overexpression delayed endothelial cell senescence and atherosclerosis progression in ApoE-/- mice. These results revealed an important role for circGNAQ in cellular senescence and provide novel insight into the role of circRNAs in atherosclerosis progression.
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