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OLFM4 is a direct target of the cGAS-STING pathway and acts as an extracellular inhibitor for the Hippo signaling in EBV-associated cancer

ABSTRACT: To investigate protein components of MVs in EBVaGC, we collected clinical tissue samples of 3 EBV+ and 3 EBV- gastric cancer patients, and isolated MVs from these samples. Then performed 4D-label free quantitative proteomics analysis for each isolated MVs. Raw files of 6 samples are included in subproject.

ORGANISM(S): Homo Sapiens

SUBMITTER: Zhaocai Zhou

PROVIDER: PXD057977 | iProX | Mon Nov 18 00:00:00 GMT 2024

REPOSITORIES: iProX

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Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression.

Wen Fuping F Han Yi Y Zhang Hui H Zhao Zhangting Z Wang Wenjia W Chen Fan F Qin Weimin W Ju Junyi J An Liwei L Meng Yan Y Yang Jie J Tang Yang Y Zhao Yun Y Zhang Huanhu H Li Feng F Bai Wenqi W Xu Yuanzhi Y Zhou Zhaocai Z Jiao Shi S

Nature communications 20241204 1

Extracellular vesicles (EVs) are known to mediate cell communications and shape tumor microenvironment. Compared to the well-studied small EVs, the function of large microvesicles (MVs) during tumorigenesis is poorly understood. Here we show the proteome of MVs in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), and identify olfactomedin 4 (OLFM4) is induced by EBV infection and secreted via MVs to promote tumor progression through Hippo signaling. Specifically, OLFM4 is a target gen ...[more]

PMID: 39627192

Similar Datasets

OLFM4 is a direct target of the cGAS-STING pathway and acts as an extracellular inhibitor for the Hippo signaling in EBV-associated cancer

Project description:Transcriptome analysis of the function of OLFM4 MV on gastric cancer HGC-27 cells

2024-09-18 | GSE240275 | GEO

cGAS/STING axis mediates a topoisomerase II inhibitor-induced tumor immunogenicity.

Project description:Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death (ICD)-inducing drugs available that can kill cancer cells, enhance tumor immunogenicity, increase the in vivo immune infiltration, and thereby boosting a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immuno-stimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still investigational. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and T cell activation assay. We identified that teniposide, a DNA topoisomerase II inhibitor, could induce high mobility group box 1 (HMGB1) release and type I interferon signaling in tumor cells, and teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling including NF-κB activation and STING-dependent type I interferon signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 on multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity, and enabled a potential chemo-immunotherapeutic approach to potentiate the therapeutic efficacy of anti-PD1 immunotherapy.

| S-EPMC6819145 | biostudies-literature

A novel inactivated whole-cell Pseudomonas aeruginosa vaccine that acts through the cGAS-STING pathway.

Project description:Pseudomonas aeruginosa infection continues to be a major threat to global public health, and new safe and efficacious vaccines are needed for prevention of infections caused by P. aeruginosa. X-ray irradiation has been used to prepare whole-cell inactivated vaccines against P. aeruginosa infection. However, the immunological mechanisms of X-ray-inactivated vaccines are still unclear and require further investigation. Our previous study found that an X-ray-inactivated whole-cell vaccine could provide protection against P. aeruginosa by boosting T cells. The aim of the present study was to further explore the immunological mechanisms of the vaccine. Herein, P. aeruginosa PAO1, a widely used laboratory strain, was utilized to prepare the vaccine, and we found nucleic acids and 8-hydroxyguanosine in the supernatant of X-ray-inactivated PAO1 (XPa). By detecting CD86, CD80, and MHCII expression, we found that XPa fostered dentritic cell (DC) maturation by detecting. XPa stimulated the cGAS-STING pathway as well as Toll-like receptors in DCs in vitro, and DC finally underwent apoptosis and pyroptosis after XPa stimulation. In addition, DC stimulated by XPa induced CD8+ T-cell proliferation in vitro and generated immunologic memory in vivo. Moreover, XPa vaccination induced both Th1 and Th2 cytokine responses in mice and reduced the level of inflammatory factors during infection. XPa protected mice in pneumonia models from infection with PAO1 or multidrug-resistant clinical isolate W9. Chronic obstructive pulmonary disease (COPD) mice immunized with XPa could resist PAO1 infection. Therefore, a new mechanism of an X-ray-inactivated whole-cell vaccine against P. aeruginosa infection was discovered in this study.

| S-EPMC8484301 | biostudies-literature

OLFM4 is a direct target of the cGAS-STING pathway and acts as an extracellular inhibitor for the Hippo signaling in EBV-associated cancer

Project description:Gene expression profile regulated by EBV infection

2024-09-18 | GSE240274 | GEO

OLFM4 is a direct target of the cGAS-STING pathway and acts as an extracellular inhibitor for the Hippo signaling in EBV-associated cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-18 | GSE240276 | GEO

Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.

Project description:Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

| S-EPMC11300882 | biostudies-literature

cGAS-STING pathway in cancer biotherapy.

Project description:The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.

| S-EPMC7472700 | biostudies-literature

Microglial cGAS-STING signaling underlies glaucoma pathogenesis.

Project description:Characterized by progressive degeneration of retinal ganglion cells (RGCs) and vision loss, glaucoma is the primary cause of irreversible blindness, incurable and affecting over 78 million patients. However, pathogenic mechanisms leading to glaucoma-induced RGC loss are incompletely understood. Unexpectedly, we found that cGAS-STING (2'3'-cyclic GMP-AMP-stimulator of interferon genes) signaling, which surveils displaced double-stranded DNA (dsDNA) in the cytosol and initiates innate immune responses, was robustly activated during glaucoma in retinal microglia in distinct murine models. Global or microglial deletion of STING markedly relieved glaucoma symptoms and protected RGC degeneration and vision loss, while mice bearing genetic cGAS-STING supersensitivity aggravated retinal neuroinflammation and RGC loss. Mechanistically, dsDNA from tissue injury activated microglial cGAS-STING signaling, causing deleterious macroglia reactivity in retinas by cytokine-mediated microglia-macroglia interactions, progressively driving apoptotic death of RGCs. Remarkably, preclinical investigations of targeting cGAS-STING signaling by intraocular injection of TBK1i or anti-IFNAR1 antibody prevented glaucoma-induced losses of RGCs and vision. Therefore, we unravel an essential role of cGAS-STING signaling underlying glaucoma pathogenesis and suggest promising therapeutic strategies for treating this devastating disease.

| S-EPMC11388346 | biostudies-literature

Attenuation of cGAS/STING activity during mitosis.

Project description:The innate immune system recognizes cytosolic DNA associated with microbial infections and cellular stress via the cGAS/STING pathway, leading to activation of phospho-IRF3 and downstream IFN-I and senescence responses. To prevent hyperactivation, cGAS/STING is presumed to be nonresponsive to chromosomal self-DNA during open mitosis, although specific regulatory mechanisms are lacking. Given a role for the Golgi in STING activation, we investigated the state of the cGAS/STING pathway in interphase cells with artificially vesiculated Golgi and in cells arrested in mitosis. We find that whereas cGAS activity is impaired through interaction with mitotic chromosomes, Golgi integrity has little effect on the enzyme's production of cGAMP. In contrast, STING activation in response to either foreign DNA (cGAS-dependent) or exogenous cGAMP is impaired by a vesiculated Golgi. Overall, our data suggest a secondary means for cells to limit potentially harmful cGAS/STING responses during open mitosis via natural Golgi vesiculation.

| S-EPMC7368095 | biostudies-literature

Porcine cGAS-STING signaling induced autophagy inhibits STING downstream IFN and apoptosis.

Project description:The innate immune DNA sensing cGAS-STING signaling pathway has been widely recognized for inducing interferons (IFNs) and subsequent antiviral state. In addition to IFN, the cGAS-STING pathway also elicits other cell autonomous immunity events including autophagy and apoptosis. However, the downstream signaling events of this DNA sensing pathway in livestock have not been well defined. Here, we systematically analyzed the porcine STING (pSTING) induced IFN, autophagy and apoptosis, revealed the distinct dynamics of three STING downstream events, and established the IFN independent inductions of autophagy and apoptosis. Further, we investigated the regulation of autophagy on pSTING induced IFN and apoptosis. Following TBK1-IRF3-IFN activation, STING induced Atg5/Atg16L1 dependent autophagy through LIR motifs. In turn, the autophagy likely promoted the pSTING degradation, inhibited both IFN production and apoptosis, and thus restored the cell homeostasis. Therefore, this study sheds lights on the molecular mechanisms of innate immunity in pigs.

| S-EPMC9608012 | biostudies-literature

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