Similar Datasets
Project description:Using single-cell RNA-sequencing (scRNA-seq), we characterize diverse immune cell infiltrates that remodel the tissue microenvironment following senescence activation in female Znrf3 cKO mice.
2023-04-03 | GSE201126 | GEO
Project description:Using the adrenal gland as a model, we investigated the interplay between genetic Znrf3 inactivation and the aging microenvironment. We hypothesized that SF1-Cre-driven Znrf3 cKO mice would progress from adrenal hyperplasia to carcinoma with age. Unexpectedly, after an initial phase of hyperplasia, we found that Znrf3 cKO adrenals steadily regress over time. We demonstrate this phenotypic switch from hyperplasia to regression is driven by activation of cellular senescence and a subsequent senescence-associated secretory phenotype (SASP).
2023-04-03 | GSE201125 | GEO
Project description:Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner
| PRJNA828523 | ENA
Project description:Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner [scRNA-seq]
| PRJNA828535 | ENA
Project description:Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner [bulk RNA-seq]
| PRJNA828536 | ENA
Project description:UnlabelledOncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes while simultaneously activating 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.SignificanceThis study reveals how cells undergoing oncogene-induced senescence acquire a distinctive enhancer landscape that includes formation of super-enhancers adjacent to immune-modulatory genes required for paracrine immune activation. This process links BRD4 and super-enhancers to a tumor-suppressive immune surveillance program that can be disrupted by small molecule inhibitors of the bromo and extra terminal domain family of proteins. Cancer Discov; 6(6); 612-29. ©2016 AACR.See related commentary by Vizioli and Adams, p. 576This article is highlighted in the In This Issue feature, p. 561.
| S-EPMC4893996 | biostudies-literature
Project description:Pathological cardiac hypertrophy and cardiac fibrosis are remodeling events that result in mechanical stiffness and pathophysiological changes of the myocardium. Both humans and animal models display a sexual dimorphism where females are more protected from pathological remodeling. Fibroblast growth factor 2 (FGF2) mediates cardiac hypertrophy, cardiac fibrosis and protection against cardiac injury and is made in high molecular weight and low molecular weight isoforms (Hi FGF2 and Lo FGF2, respectively). Although some light has been shed on isoform-specific functions in cardiac pathophysiology, their roles in pathologic cardiac remodeling have yet to be determined. We tested the hypothesis that Lo FGF2 and Hi FGF2 modulate pathological cardiac remodeling in an isoform-specific manner. Young adult male and female mice between 8-12 weeks of age of mixed background that were deficient in either Hi FGF2 or Lo FGF2 (Hi KO or Lo KO, respectively) were subjected to daily injections of isoproterenol (Iso) for four days after which their hearts were compared to wildtype cohorts. Post-Iso treatment, female Lo KO hearts don't exhibit significant differences in their hypertrophic and fibrotic response, while female Hi KO hearts present with a blunted hypertrophic response. In male animals Lo KO hearts present with an exacerbated fibrotic response and increased alpha-smooth muscle actin protein expression while Hi KO hearts present with a blunted fibrotic response and increased atrial natriuretic factor protein expression Thus, in female hearts Hi FGF2 mediate cardiac hypertrophy while in male hearts Lo FGF2 and Hi FGF2 display an antithetical role in cardiac fibrosis where Lo FGF2 is protective while Hi FGF2 is damaging. In conclusion, cardiac remodeling following catecholamine overactivation is modulated by FGF2 in isoform- and sex-specific manners.
| S-EPMC3827774 | biostudies-literature
Project description:Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS-ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.
| S-EPMC9186388 | biostudies-literature
Project description:KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8+ T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.
| S-EPMC7278897 | biostudies-literature
Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMCs) 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 p16 fl/fl -Cdh5(PAC)-Cre ERT2 (p16 iΔEC ) 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 lungs 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 p16 iΔEC mouse lung EC-derived exosomes inhibit the effects. These results suggest that endothelial senescence modulates TWIST1-PDGFB signaling and controls vascular remodeling in PH.
| S-EPMC9530050 | biostudies-literature