Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

LINE-1 ORF1p immune evasion mechanisms in pancreatic ductal adenocarcinoma

ABSTRACT: Repeat element viral mimicry is a common feature in pancreatic ductal adenocarcinoma (PDAC) that require mechanisms to manage this repeat “viral” load and attenuate innate immune responses. Here, we show that the LINE-1 ORF1 protein (ORF1p) in PDAC cells plays a role in shielding repeat RNAs from activating a pathogen recognition receptor (PRR)-mediated antiviral response that is independent of retrotransposition. Suppression of ORF1p using short hairpin RNA induces innate immune responses through the dsRNA sensors RIG-I and MAVS. Low ORF1p PDAC cell lines have suppressed expression of PRRs demonstrating convergent mechanisms to suppress innate immune signaling. Localization of ORF1p in processing bodies (P-bodies) with the dsRNA helicase MOV10 were found important for these antiviral responses. Loss of ORF1p resulted in significant growth reduction in tumorspheres and mouse xenografts with an enriched epithelial cell state, and high ORF1p expression was associated with worsened survival in a cohort of human PDAC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287105 | GEO | 2025/01/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Profiling of RNAs associated with LINE-1 ORF1p in pancreatic ductal adenocarcinoma

Project description:Repeat element viral mimicry is a common feature in pancreatic ductal adenocarcinoma (PDAC) that require mechanisms to manage this repeat “viral” load and attenuate innate immune responses. Here, we show that the LINE-1 ORF1 protein (ORF1p) in PDAC cells plays a role in shielding repeat RNAs from activating a pathogen recognition receptor (PRR)-mediated antiviral response that is independent of retrotransposition. Suppression of ORF1p using short hairpin RNA induces innate immune responses through the dsRNA sensors RIG-I and MAVS. Low ORF1p PDAC cell lines have suppressed expression of PRRs demonstrating convergent mechanisms to suppress innate immune signaling. Localization of ORF1p in processing bodies (P-bodies) with the dsRNA helicase MOV10 were found important for these antiviral responses. Loss of ORF1p resulted in significant growth reduction in tumorspheres and mouse xenografts with an enriched epithelial cell state, and high ORF1p expression was associated with worsened survival in a cohort of human PDAC patients.

2025-01-16 | GSE287102 | GEO

Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms [PDAClines_RNAseq]

Project description:To thrive, cancers must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of retrotransposable elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNA (dsRNAs) and trigger RIG-I-like receptor-associated (RLR) type-I interferon (IFN) signaling. Alu-derived dsRNA anti-correlated with pro-tumorigenic macrophage infiltration. We defined two complementary pathways whereby PDAC may adapt to such anti-tumorigenic signaling. In mutant p53 tumors, ORF1p from LINE-1 preferentially binds Alus and decreases their expression, whereas ADAR1 editing primarily reduces dsRNA formation in wild-type p53 tumors. Depletion of either ORF1p or ADAR1 reduced tumor growth in vitro. That tumors utilize multiple pathways to mitigate immunostimulatory repeats implies that the stress from their expression is a fundamental phenomenon to which PDAC, and other tumors, adapt.

2024-12-16 | GSE280866 | GEO

Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms

Project description:To thrive, cancers must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of retrotransposable elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNA (dsRNAs) and trigger RIG-I-like receptor-associated (RLR) type-I interferon (IFN) signaling. Alu-derived dsRNA anti-correlated with pro-tumorigenic macrophage infiltration. We defined two complementary pathways whereby PDAC adapt to such anti-tumorigenic signaling. In mutant p53 tumors, ORF1p from LINE-1 may preferentially bind Alus and decrease their expression, whereas ADAR1 editing primarily reduces dsRNA formation in wild-type p53 tumors. Depletion of either ORF1p or ADAR1 reduced tumor growth in vitro. That tumors utilize multiple pathways to mitigate immunostimulatory repeats implies that the stress from their expression is a fundamental phenomenon to which PDAC, and other tumors, adapt.

2024-12-16 | GSE280626 | GEO

SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA

Project description:Recognition of pathogen-derived foreign nucleic acids is central to innate immune defense. This requires discrimination between structurally highly similar self and nonself nucleic acids to avoid aberrant inflammatory responses as in the autoinflammatory disorder Aicardi-Goutires syndrome (AGS). How vast amounts of self RNA are shielded from immune recognition to prevent autoinflammation is not fully understood. Here we show that SAM domain and HD domain-containing protein 1 (SAMHD1), one of the AGS-causing genes, functions as a single-stranded RNA (ssRNA) 3«exonuclease, the lack of which causes cellular RNA accumulation. Increased ssRNA in cells leads to dissolution of RNA-protein condensates, which sequester immunogenic double-stranded RNA (dsRNA). Release of sequestered dsRNA from condensates triggers activation of antiviral type I interferon via retinoic acid-inducible gene I-like receptors. Our results establish SAMHD1 as a key regulator of cellular RNA homeostasis and demonstrate that buffering of immunogenic self RNA by condensates regulates innate immune responses.

2023-02-06 | PXD035182 | Pride

Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA

Project description:Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the innate immune receptors that recognize viral double-stranded RNA (dsRNA) and initiate antiviral immune responses with the potential of triggering systemic inflammation and immunopathology. How the functions of the dsRNA receptors and their downstream effector molecules are coordinately regulated to avoid excessive immune response is poorly understood. We here demonstrate that stress granules (SGs), biomolecular condensates that form in response to various stresses including viral dsRNA, play key roles in regulating dsRNA-triggered immune response. Upon dsRNA stimulation, SGs recruit many innate immune molecules, including RIG-I-like receptors (RLRs), protein kinase R (PKR) and oligoadenylate synthases (OASes), target these molecules and dsRNA for autophagy and limit their functions through sequestration. In the absence of SGs, dsRNA stimulation results in hyperactivation of inflammatory signaling pathways, global translational arrest and bulk RNA degradation, altogether compromising the cellular capacity to restore homeostasis and triggering cell death. In contrast to most dsRNA-induced immune signaling pathways that are hyperactivated in the absence of SGs, a sub-branch of the RLR pathway (IRF3-dependent type I interferon signaling) shows time-dependent changes, where the initial spike in signaling is followed by a significant drop due to increased caspase-dependent negative feedback regulation. This highlights the role of SGs in regulating the delicate balance between the type I interferon pathway and cell death. Altogether, our data suggest that cells utilize SGs as shock absorbers to moderate antiviral innate immune response, thereby allowing cells to guard against its own immune system as well as viruses.

2021-05-06 | GSE173953 | GEO

PACT-mediated regulation of endogenous dsRNA sensing by PKR

Project description:Protein kinase R (PKR), an innate immune sensor for double-stranded RNA (dsRNA), is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a crucial and controversial role in the PKR pathway. We demonstrate that PACT is an essential negative regulator of PKR against endogenous dsRNA ligands like inverted repeat Alu RNAs, which satisfy PKR’s selectivity for long dsRNA and robustly activate PKR in the absence of PACT. PACT employs an unusual inhibitory mechanism sensitive to dsRNA length and concentration, inhibiting PKR through low-affinity interactions most effective when both are bound to the same dsRNA molecule. Consequently, PACT’s inhibition of PKR is more robust when dsRNA is longer and less abundant, with minimal effect on abundant or short dsRNA. Thus, PACT functions as a rheostat, setting the PKR activation threshold for long endogenous dsRNA without altering its inherent activity.

2024-06-16 | GSE269684 | GEO

The RNA editing enzyme ADAR1 is a key regulatory of innate immune responses to RNA

Project description:The ADAR RNA editing enzymes deaminate adenosine bases to inosines in cellular RNAs, recoding open reading frames. Human ADAR1 mutations cause Aicardi-Goutieres Syndrome (AGS) and Adar1 mutant mice showing an aberrant interferon response and death by embryonic day E12.5 model the human disease. Searches have not identified key ADAR1 RNA editing sites recoding immune/haematopoietic proteins but editing is widespread in Alu sequences. We show that Adar1 embryonic lethality is rescued in Adar1; Mavs double mutant mice in which general antiviral responses to cytoplasmic dsRNA are prevented. We propose that inosine bases are epigenetic marks identifying cellular RNA as innate immune ÒselfÓ. Consistent with this idea we show that an editing-active cytoplasmic ADAR is required to prevent aberrant immune responses in Adar1 mutant mouse embryo fibroblasts. No dramatic increase in repetitive transcripts is observed. AGS mutations in ADAR1 affect editing by the interferon-inducible cytoplasmic ADAR1 isoform. RNA-seq expression profiling in Adar1 and Adar1/Mavs knockout mice embryos.

2014-12-19 | E-GEOD-62917 | biostudies-arrayexpress

Human LINE-1 ORF1p complex LC-MS/MS

Project description:Host proteins regulate LINE-1 (L1) retrotransposition. Here, we use immunoprecipitation followed by liquid chromatography-tandem mass spectrometry to identify proteins that associate with the L1 ORF1-encoded protein (ORF1p) in ribonucleoprotein particles.

2023-03-11 | PXD038851 | Pride

Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation

Project description:Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded RNA (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report that human neurons intrinsically carry exceptionally high levels of immunostimulatory dsRNAs and identify long 3'UTRs as giving rise to neuronal dsRNA structures. We found that the neuron-enriched ELAVL family of genes (ELAVL2, -3, -4) can increase 1) 3'UTR length, 2) dsRNA load, and 3) activation of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3. In wild-type neurons, neuronal dsRNAs signaled through PRRs to induce tonic production of the antiviral type I interferon. Depleting ELAVL2 in WT neurons led to global shortening of 3'UTR length, reduced immunostimulatory dsRNA levels, and rendered WT neurons susceptible to herpes simplex virus and Zika virus infection. Neurons deficient in ADAR1, a dsRNA-editing enzyme mutated in the neuroinflammatory disorder Aicardi-Goutières syndrome, exhibited intolerably high levels of dsRNA that triggered PRR mediated toxic inflammation and neuronal death. Depleting ELAVL2 in ADAR1 knockout neurons led to prolonged neuron survival by reducing immunostimulatory dsRNA levels. In summary, neurons are specialized cells where PRRs constantly sense ‘self’ dsRNAs to pre-emptively induce protective antiviral immunity, but maintaining RNA homeostasis is paramount to prevent pathological neuroinflammation.

2023-10-20 | GSE214949 | GEO

Inhibiting DDX3X triggers tumor-intrinsic type I interferon response and enhances anti-tumor immunity

Project description:Accumulating evidence has shown that cellular double-stranded RNAs (dsRNAs) induce antiviral innate immune responses in human normal and malignant cancer cells. However, it is not fully understood how endogenous ‘self’ dsRNA homeostasis is regulated in the cell. Here, we show that an RNA-binding protein, DEAD-box RNA helicase 3X (DDX3X), prevents the aberrant accumulation of cellular dsRNAs. Loss of DDX3X induces dsRNA sensor-mediated type I interferon signaling and innate immune response in breast cancer cells due to abnormal cytoplasmic accumulation of dsRNAs. Dual depletion of DDX3X and a dsRNA-editing protein, ADAR1 synergistically activates the cytosolic dsRNA pathway in breast cancer cell. Moreover, inhibiting DDX3X enhances the antitumor activity by increasing tumor intrinsic-type I interferon response, antigen presentation, and tumor-infiltration of cytotoxic T cells as well as dendritic cells in breast tumors, which may lead to the development of breast cancer therapy by targeting DDX3X in combination with immune checkpoint blockade. To assess the impact of DDX3X on the gene expression in the breast cancer, we stably depleted DDX3X in breast cancer MCF7 cells using a short hairpin RNA (shRNA)-mediated knockdown, and performed a genome-wide transcriptome analysis using a next-generation RNA deep sequencing.

2020-09-03 | GSE157323 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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