Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA747704 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15182200_1.fastq.gz | Fastqsanger.gz | |||
| SRR15182200_2.fastq.gz | Fastqsanger.gz | |||
| SRR15182201_1.fastq.gz | Fastqsanger.gz | |||
| SRR15182201_2.fastq.gz | Fastqsanger.gz | |||
| SRR15182202_1.fastq.gz | Fastqsanger.gz |
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Project description:We report the ability of a gene expression signature to predict response to neoadjuvant chemotherapy in early breast cancer, and also describe transcriptomic changes during treatment
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Project description:The innate immune cGAS-STING pathway has emerged as an important signaling system in the organismal defense against viral and bacterial infections, inflammatory responses to cellular damage, regulation of autophagy, as well as in tumor immunosurveillance. Such key functions of the cGAS-STING pathway make it an attractive target for pharmacological intervention in disease treatments and in controlling inflammation and immunity. Here, we show that urolithin A (UA), an ellagic acid metabolite, exerts a profound effect on the expression of STING and enhances cGAS-STING activation and STING-related autophagy in response to cytosolic DNA in human cell lines. Animal laboratory models and limited human trials have reported no obvious adverse effects of UA administration. Thus, the use of UA alone or in combination with other pharmacological compounds may present a potential therapeutic approach in the treatment of human diseases that involves aberrant activation of the cGAS-STING pathway or accumulation of cytosolic DNA and warrants further investigation in relevant transgenic animal models.
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Project description:Stimulator of interferon genes (STING), the central hub protein of the cGAS-STING signaling, is essential for type I IFN production of innate immunity. However, prolonged or excessive activation of STING is highly related to autoimmune diseases, most of which exhibit the hallmark of elevated expression of type I interferons and IFN-stimulated genes (ISGs). Thus, the activity of STING must be stringently controlled to maintain immune homeostasis. Here, we reported that CK1α, a protein serine/threonine kinase, was essential to prevent the over-activation of STING-mediated type I IFN signaling through autophagic degradation of STING. Mechanistically, CK1α interacted with STING upon the cGAS-STING pathway activation and promoted STING autophagic degradation by enhancing the phosphorylation of p62 at serine 349, which was critical for p62 mediated STING autophagic degradation. Consistently, SSTC3, a selective CK1α agonist, significantly attenuated the response of the cGAS-STING signaling by promoting STING autophagic degradation. Importantly, pharmaceutical activation of CK1α using SSTC3 markedly repressed the systemic autoinflammatory responses in the Trex1-/- mouse autoimmune disease model and effectively suppressed the production of IFNs and ISGs in the PBMCs of SLE patients. Taken together, our study reveals a novel regulatory role of CK1α in the autophagic degradation of STING to maintain immune homeostasis. Manipulating CK1α through SSTC3 might be a potential therapeutic strategy for alleviating STING-mediated aberrant type I IFNs in autoimmune diseases.
2024-01-31 | GSE226593 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234421 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234420 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234419 | GEO
Project description:Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
2023-08-20 | GSE234417 | GEO
Project description:Aims/hypothesis cGAS (cyclic GMP-AMP synthase) has been implicated in various cellular processes, but its role in β-cell proliferation and diabetes is not fully understood. This study investigates the impact of cGAS on β-cell proliferation, particularly in the context of diabetes. Methods Utilizing mouse models, including cGAS and STING (stimulator of interferon genes) knockout mice, we explored the role of cGAS in β-cell function. This involved β-cell-specific cGAS knockout (cGASβKO) mice, created by breeding cGAS floxed mice with transgenic mice expressing Cre recombinase under the insulin II promoter. We analyzed cGAS expression in diabetic mouse models, evaluated the effects of cGAS deficiency on glucose tolerance, and investigated the molecular mechanisms underlying these effects through RNA sequencing. Results Our study found that cGAS expression is upregulated in the islets of diabetic mice and in response to high glucose conditions in MIN6 cells. Global cGAS deficiency enhanced glucose tolerance, while β-cell-specific cGAS knockout improved glucose intolerance under high-fat diet conditions. Interestingly, STING knockout did not affect pancreatic β-cell mass, suggesting a STING-independent mechanism for cGAS's role in β-cells. Further analyses revealed that cGAS deficiency leads to increased β-cell proliferation and reduced expression of CEBPβ, a known suppressor of β-cell proliferation. This effect appears to be mediated by a STING-independent pathway and is specific to pancreatic tissue. Conclusions/interpretation Our findings indicate that cGAS plays a pivotal role in modulating β-cell proliferation and glucose homeostasis, potentially through regulating CEBPβ expression in a STING-independent manner. This study highlights the importance of cGAS in diabetes pathology and suggests it as a potential therapeutic target for enhancing β-cell proliferation in diabetes treatment.
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Project description:The cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of HIV-1 and initiate the antiviral immune response through cGAS–STING–TBK1–IRF3–type I IFN (IFN-I) signaling cascade. HIV-1 uses several strategies to interfere with the host immune molecules and mediate immune evasion. However, the potential role of HIV-1 proteins in cGAS–STING signaling remains unclear. Here we report that the HIV-1 protein p6 suppresses HIV-1-stimulated expression of IFN-I and promotes the immune evasion. Mechanistically, p6 bound with STING and inhibited the activation of STING and the interaction between STING and TBK1. Moreover, the glutamylation of p6 at Glu6 residue inhibited the interaction between STING and TRIM32 or AMFR, which subsequently suppressed the K27- and K63-linked polyubiquitination of STING at Lys337, therefore inhibited STING activation and type I IFN production, while the mutation of Glu6 residue lost the inhibitory effect. However, CoCl2, an agonist for cytosolic carboxypeptidases (CCPs), counteracted the glutamylation of Glu6 residue of p6 and promoted IFN-I production to block the immune evasion of HIV-1. These findings not only reveal a previously unknown mechanism through which an HIV-1 protein mediate immune evasion, but also provide a new therapeutic drug candidate to treat HIV-1 infection.
2021-11-25 | GSE189384 | GEO
Project description:Colorectal cancer is the second leading cause of cancer mortality in the US. Although immune checkpoint blockade therapies such as anti-PD-1/PD-L1 have had successes in some patients, the response rate is still low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cGAS/STING pathway and increases expression of interferon β (IFNβ) and IFNβ-regulated genes including CXCL10. Inhibition of ATM, but not ATR, results in a synergistic increase in IFNβ expression, suggesting that riluzole-dependent double strand breaks contribute to cGAS/STING activation. Knockout of cGAS or STING significantly attenuated expression of IFNβ and CXCL10 and nearly abolished suppression of tumor growth. Riluzole failed to increase intratumoral CD8+ T cells in STING knockout tumors. These results indicate that riluzole recruits CD8+ T cells into the tumor microenvironment through tumor cell intrinsic STING activation. When riluzole was combined with a PD-1 antibody, the treatment was more effective in suppressing tumor growth in vivo. Taken together, our studies indicate that riluzole inhibits tumor growth through the activation of cGAS/STING signaling and may increase the efficacy of anti-PD-1/PD-L1 therapies in colon cancer.
2024-09-27 | GSE251940 | GEO