Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer
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ABSTRACT:
PROVIDER: PRJNA594360 | ENA |
REPOSITORIES: ENA
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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: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.
2020-02-03 | GSE141684 | GEO
Project description:Natural killer (NK) cells are lymphocytes that participate in immune responses through their cytotoxic activity and secretion of cytokines and chemokines. They can be activated by interaction with ligands on target cells or by soluble mediators such as cytokines. In addition, soluble HLA-G, a major histocompatibility complex molecule secreted by fetal trophoblast cells during early pregnancy, stimulates resting NK cells to secrete proinflammatory and proangiogenic factors. Human NK cells are abundant in uterus, where they remain after implantation. Soluble HLA-G is endocytosed into early endosomes of NK cells where its receptor, CD158d, initiates a signaling cascade through DNA-PKcs, Akt and NF-kB3. The physiological relevance of this endosomal signaling pathway, and how the fate and function of NK cells during early pregnancy is regulated, is unknown. Here we show that soluble agonists of CD158d trigger DNA damage response signaling and p21 (CIP1/WAF1) expression to promote senescence in primary NK cells. CD158d engagement resulted in morphological alterations in cell size and shape, chromatin remodeling, and survival in the absence of proliferation, all hallmarks of senescence. Microarray analysis revealed a senescence signature of upregulated genes upon sustained activation through CD158d. The proinflammatory and proangiogenic factors secreted by these metabolically active NK cells are part of a senescence associated secretory phenotype (SASP) that promoted tissue remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. We propose that ligand-induced senescence is a molecular switch for the sustained activation of NK cells in response to soluble HLA-G for the purpose of remodeling the maternal vasculature in early pregnancy. Time series (4 hr, 16 hr, 64 hr) of NK cells treated with agonist (anti-CD158d mAb) or control. NK cells were from 4 donors.
2012-12-03 | E-GEOD-35330 | biostudies-arrayexpress
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.
2022-10-15 | PXD033549 | Pride
Project description:Hepatitis C virus scarring of the epigenome and creates targetable vulnerabilities following viral clearance
| PRJNA706410 | ENA
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:Natural killer (NK) cells are lymphocytes that participate in immune responses through their cytotoxic activity and secretion of cytokines and chemokines. They can be activated by interaction with ligands on target cells or by soluble mediators such as cytokines. In addition, soluble HLA-G, a major histocompatibility complex molecule secreted by fetal trophoblast cells during early pregnancy, stimulates resting NK cells to secrete proinflammatory and proangiogenic factors. Human NK cells are abundant in uterus, where they remain after implantation. Soluble HLA-G is endocytosed into early endosomes of NK cells where its receptor, CD158d, initiates a signaling cascade through DNA-PKcs, Akt and NF-kB3. The physiological relevance of this endosomal signaling pathway, and how the fate and function of NK cells during early pregnancy is regulated, is unknown. Here we show that soluble agonists of CD158d trigger DNA damage response signaling and p21 (CIP1/WAF1) expression to promote senescence in primary NK cells. CD158d engagement resulted in morphological alterations in cell size and shape, chromatin remodeling, and survival in the absence of proliferation, all hallmarks of senescence. Microarray analysis revealed a senescence signature of upregulated genes upon sustained activation through CD158d. The proinflammatory and proangiogenic factors secreted by these metabolically active NK cells are part of a senescence associated secretory phenotype (SASP) that promoted tissue remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. We propose that ligand-induced senescence is a molecular switch for the sustained activation of NK cells in response to soluble HLA-G for the purpose of remodeling the maternal vasculature in early pregnancy.
2012-12-03 | GSE35330 | GEO
Project description:SETD2 Loss Creates A Permissive Epigenetic Landscape that Promotes Kidney Cancer Metastasis and Engenders Therapeutic Vulnerabilities
| PRJNA610874 | ENA
Project description:We analyzed a panel of 13 cancer cell lines rendered senescent by either etoposide (7 day treatment) or alisertib (7 and 14 day treatment). We aimed to find common vulnerabilities to induce cell death, and shared features that would allow unambiguous identification of the senescent state in the context of a cancerous phenotype. The samples were treated for the given duration, followed by 24 hours without drug before RNA was extracted. The senescence phenotype was assessed by B-gal staining, growth arrest and morphology.
2021-07-18 | E-MTAB-9970 | biostudies-arrayexpress