Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

ABSTRACT: The IRE1α-XBP1 arm of the unfolded protein response (UPR) has emerged as a central orchestrator of malignant progression and immunosuppression in various cancer types. Yet the role of this pathway in non-small cell lung cancer (NSCLC) has remained largely unexplored. Using an RNA-seq based computational XBP1s detection method applied to TCGA datasets, we uncovered that expression of the IRE1a-generated XBP1s mRNA isoform predicts poor survival in NSCLC patients. Ablation of IRE1a in malignant cells delayed tumor progression and extended survival in an XBP1-dependent fashion in mouse models of NSCLC. This protective effect was accompanied by marked alterations in both lymphoid and myeloid intratumoral cell subsets that elicited durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustained mPGES-1 expression, enabling production of the immunosuppressive lipid mediator PGE2 in the tumor microenvironment (TME). Accordingly, restoring mPGES-1 expression in IRE1αKO cancer cells rescued normal tumor progression. By identifying the dominant transcriptional networks controlled by IRE1α in mouse lung tumors, we further developed a new gene signature that predicted immune cell infiltration and overall survival in human NSCLC. Hence, our study unveils a key immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC.

ORGANISM(S): Mus musculus

PROVIDER: GSE202939 | GEO | 2022/05/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Dual role of the unfolded protein response in the therapeutic effect of AZD1775 on TP53 mutant high grade serous ovarian cancer

Project description:we demonstrate that the WEE1 inhibitor AZD1775 triggers endoplasmic reticulum (ER) stress and activates the PERK and IRE1α branches of the unfolded protein response (UPR) in TP53 mutant HGSOC cells. Upon AZD1775 treatment, PERK facilitates apoptotic signaling in these cells via activating CHOP, whereas IRE1α-induced spliced XBP1 (XBP1s) confers survival in response to WEE1 inhibition. Our data uncover an important dual role of UPR in TP53 mutant HGSOC cells in response to AZD1775, where additional inhibition of IRE1α-XBP1s signaling may offer synergistic efficacy.

2021-02-10 | GSE166417 | GEO

Identification of global XBP1s target gene expression in human prostate cancer cells

Project description:To gain insight into the global XBP1s target gene profile in prostate cancer cells, we performed RNA-seq analysis in LNCaP cells upon either XBP1 siRNA-mediated knockdown (siXBP1) or MKC8866-mediated IRE1α inhibition.

2018-10-30 | GSE103864 | GEO

IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain

Project description:The IRE1α-XBP1 arm of the unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis, but also controls UPR-independent processes such as cytokine production and lipid metabolism. Yet, the physiological consequences of IRE1α-XBP1 activation in immune cells remain largely unexplored. Here, we report that leukocyte-intrinsic IRE1α-XBP1 signaling drives prostaglandin biosynthesis and pain. Transcriptomic analyses revealed that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated via pattern recognition receptors. Inducible biosynthesis of prostaglandins, including PGE2, was markedly decreased in myeloid cells lacking IRE1α or XBP1, but not altered in the absence of the two other ER stress sensors PERK and ATF6. Mechanistically, IRE1α-activated XBP1 bound to and directly induced the expression of human PTGS2 and PTGES to enable PGE2 generation. Mice selectively lacking IRE1α-XBP1 in leukocytes, or treated with pharmacological IRE1α inhibitors, failed to induce PGE2 upon challenge with inflammatory stimuli and demonstrated reduced behavioral pain responses in PGE2-dependent models of pain. Our study uncovers an unexpected role for IRE1α-XBP1 as a key mediator of prostaglandin biosynthesis and indicates that targeting this pathway may represent an alternative approach to control pain.

2020-05-16 | GSE131404 | GEO

The IRE1α-XBP1 Pathway of the Unfolded Protein Response is Required for Adipogenesis

Project description:Signaling cascades during adipogenesis culminate in the expression of two essential adipogenic factors, PPARγ and C/EBPα. Here we demonstrate that the IRE1α-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for adipogenesis. Indeed, XBP1-deficient mouse embryonic fibroblasts and 3T3-L1 cells with XBP1 or IRE1α knockdown exhibit profound defects in adipogenesis. Intriguingly, C/EBPβ, a key early adipogenic factor, induces Xbp1 expression by directly binding to its proximal promoter region. Subsequently, XBP1 binds to the promoter of Cebpa and activates its gene expression. The posttranscriptional splicing of Xbp1 mRNA by IRE1α is required as only the spliced form of XBP1 (XBP1s) rescues the adipogenic defect exhibited by XBP1-deficient cells. Taken together, our data show that the IRE1α-XBP1 pathway plays a key role in adipocyte differentiation by acting as a critical regulator of the morphological and functional transformations during adipogenesis.

2009-04-25 | GSE15771 | GEO

IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity

Project description:Tumors evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function. However, it remains unclear how intratumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer (OvCa), an aggressive malignancy refractory to standard treatments and current immunotherapies, induces Endoplasmic Reticulum (ER) stress and activation of the IRE1α-XBP1 arm of the Unfolded Protein Response (UPR)10,11 in T cells to control their mitochondrial respiration and anti-tumor function. XBP1 upregulation in T cells isolated from human OvCa specimens was associated with decreased intratumoral T cell infiltration and reduced IFNG mRNA expression. Malignant ascites fluid obtained from OvCa patients inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, leading to IRE1α/XBP1-driven suppression of mitochondrial activity and IFN- production. Mechanistically, XBP1 induction limited the influx of glutamine necessary to sustain T cell mitochondrial respiration under glucose-deprived conditions by regulating the abundance of glutamine carriers. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to OvCa ascites. XBP1-deficient T cells in the metastatic OvCa milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, OvCa-bearing mice lacking XBP1 selectively in T cells demonstrated superior anti-tumor immunity, delayed malignant progression and increased overall survival. Therefore, controlling ER stress or targeting IRE1α-XBP1 signaling may help restore T cell metabolic fitness and anti-tumor capacity in cancer hosts.

2018-10-18 | GSE118430 | GEO

The unfolded protein response gene Ire1α is required for tissue renewal and normal differentiation in the mouse tongue and esophagus

Project description:The IRE1α-XBP1s signaling branch of the unfolded protein response is a well-characterized survival pathway that allows cells to adapt to and resolve endoplasmic reticulum stress. Recent data has broadened our understanding of IRE1α-XBP1s signaling beyond a stress response and revealed a physiological mechanism required for the differentiation and maturation of a wide variety of cell types. Here we provide evidence that the IRE1α-XBP1s signaling pathway is required for the proliferation and maturation of basal keratinocytes in the mouse tongue and esophageal epithelium. Mice with conditional targeted deletion of either IRE1α or XBP1 in keratin 14 expressing basal keratinocytes displayed severe thinning of the lingual and esophageal mucosa that rendered them unable to eat. In IRE1α null epithelium harvested at an earlier timepoint, genes regulating cell proliferation, cell-cell adhesion, and keratinization were significantly downregulated; indirect immunofluorescence revealed fewer proliferating basal keratinocytes, downregulation of E-Cadherin, and thinning of the loricrin-positive granular and cornified layers. The number of Tp63 positive basal keratinocytes was reduced in the absence of IRE1α, and expression of the Wnt pathway transcription factor LEF1, which is required for the proliferation of lingual transit amplifying cells, was also significantly downregulated at the transcript and protein level. Together these results reveal an essential role for IRE1α-XBP1s in the maintenance of the stratified squamous epithelial tissue of the tongue and esophagus.

2022-09-30 | GSE205488 | GEO

CARM1 determines endoplasmic reticulum stress response by controlling XBP1 in ovarian cancer [CUT&RUN]

Project description:Cancer cells exploit adaptive responses such as endoplasmic reticulum (ER) stress to support their survival. ER stress response is mediated in part by the ER-localized transmembrane sensor IRE1α endoribonuclease and its substrate XBP1 to regulate XBP1 target gene expression. However, the mechanism that controls the IRE1α/XBP1 pathway remains poorly understood. CARM1 is an oncogene that is often overexpressed in a number of cancer types including ovarian cancer. Here we report that CARM1 determines ER stress response by controlling the IRE1α/XBP1 pathway. Genome-wide profiling revealed that CARM1 regulates XBP1 target gene expression during ER stress response. CARM1 directly interacts with XBP1. Inhibition of the IRE1α/XBP1 pathway was effective in ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model.

2021-08-11 | GSE157117 | GEO

CARM1 determines endoplasmic reticulum stress response by controlling XBP1 in ovarian cancer [RNA-seq]

2021-08-11 | GSE157116 | GEO

Transcriptional regulation of hematopoietic stem cell progenitors and acute myeloid leukemia by the IRE1a-XBP1 pathway [overexpression]

Project description:The inositol-requiring enzyme-1a (IRE1a), through its key effector transcription factor X-box binding protein-1 (XBP1), regulates cell fate and malignancy in a tissue and cell-specific manner. Here, we define the transcriptional perturbations associated with induction of XBP1 (encoded by the XBP1S gene generated by IRE1a) eficiency in patient derived human AML cells. Beyond its classical role in activating genes involved in restoring cellular proteostasis during the unfolded protein response (UPR), our transcriptome analysis reveal XBP1-dependent regulation of genes involved in diverse biological processes required for HSC homeostasis and acute myeloid leukemia (AML) development.

2023-12-30 | GSE163137 | GEO

Androgen-induced modulation of XBP1s is functionally driving part of the AR transcriptional program

Project description:Prostate cancer development and progression is largely dependent on androgen receptor (AR) signaling. AR is a hormone-dependent transcription factor, which binds to thousands of sites throughout the human genome to regulate expression of directly responsive genes, including pro-survival genes that enable tumor cells to cope with increased cellular stress. ERN1 and XBP1 – two key players of the unfolded protein response (UPR) – are among such stress-associated genes. Here, we show that XBP1 levels in primary prostate cancer are associated with biochemical recurrence in five independent cohorts. Patients who received AR targeted therapies had significantly lower XBP1 expression, whereas expression of the active form of XBP1 (XBP1s) was elevated. In vitro results show that AR-induced ERN1 expression led to increased XBP1s mRNA and protein levels. Furthermore, ChIP-seq analysis revealed that XBP1s binds enhancers upon stress stimuli regulating genes involved in UPR processes, eIF2 signaling and protein ubiquitination. We further demonstrate genomic overlap of AR and XBP1s binding sites, suggesting genomic conversion of the two signaling cascades. Transcriptomic effects of XBP1 were further studied by knockdown experiments, which lead to decreased expression of androgen-responsive genes and UPR genes. These results suggest a two-step mechanism of gene regulation, which involves androgen-induced expression of ERN1, thereby enhancing XBP1 splicing and transcriptional activity. This signaling cascade may prepare the cells for the increased protein folding, mRNA decay and translation that accompanies AR-regulated tumor cell proliferation.

2019-12-18 | GSE121880 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data