Loss of ADAR1 in tumor cells activates cDC1s and sensitizes pancreatic cancer to immunotherapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1222324 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR32308468_1.fastq.gz | Fastqsanger.gz | |||
| SRR32308468_2.fastq.gz | Fastqsanger.gz | |||
| SRR32308469_1.fastq.gz | Fastqsanger.gz | |||
| SRR32308469_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 21 |
Similar Datasets
Project description:Pancreatic cancer is notoriously resistant to immunotherapy, primarily due to inadequate antigen presentation and the exclusion of immunogenic cells from the tumor microenvironment. Strategies to enhance antigen presentation and promote the infiltration of cytotoxic CD8+ T cells may improve the efficacy of immunotherapy in pancreatic cancer. In this study, we show that ADAR1 is overexpressed in pancreatic cancer, and higher ADAR1 expression correlates with poorer survival outcomes in patients. Depletion of ADAR1 in tumor cells leads to an accumulation of endogenous double-stranded RNA (dsRNA), which triggers the MDA5-mediated type I interferon (IFN) response and results in excessive IFNβ production. Tumor-derived IFNβ then promotes the recruitment and activation of cDC1s, thereby enhancing CD8+ T cell infiltration and activation, and ultimately sensitizing pancreatic cancer to CD8+ T cell-based immunotherapy. These findings suggest that combining ADAR1 inhibition with immunotherapy may offer a promising therapeutic strategy for pancreatic cancer.
2025-04-11 | GSE289275 | GEO
Project description:We used microarrays to determine whether cDC1s from the two double KO are bona fide cDC1s, and what are the transcriptional changes within these cDC1s.
2019-06-23 | GSE123797 | GEO
Project description:Expression data from WT cDC1s, Zeb2 KO cDC1s, Nfil3 Zeb2 DKO cDC1s and Zeb2 Id2 DKO cDC1s
| PRJNA509887 | ENA
Project description:p38MAPKa stromal reprogramming sensitizes metastatic breast cancer to immunotherapy
| PRJNA865030 | ENA
Project description:Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. ZBP1 activates inflammatory cell death, PANoptosis, while ADAR1 serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining IFNs and nuclear export inhibitors (NEIs) activates ZBP1–dependent PANoptosis. ADAR1 suppresses PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wildtype mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1–dependent manner. Our findings suggest that ADAR1 suppresses ZBP1–mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to inform therapeutic strategies for cancer and other diseases.
2021-10-19 | GSE184323 | GEO
Project description:Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive and lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting TNBC from internal and external pressure, including metabolic stress. We tested the hypothesis that the iron-dependent cell death pathway, ferroptosis, is a ADAR1-protected metabolic vulnerability in TNBC by showing that ADAR1 knockdown sensitizes TNBC cells to GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled to mass spectrometry (LC-MS) to measure intracellular lipid contents, we showed that ADAR1 loss increased the abundance of polyunsaturated fatty acid phospholipids (PUFA-PL), of which peroxidation is the primary driver of ferroptosis. Transcriptomic analyses led to the discovery of the proto-oncogene MDM2 contributing to the lipid remodeling in TNBC upon ADAR1 loss. A phenotypic drug screen using a ferroptosis-focused library was performed to identify FDA-approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss to suppress TNBC tumorigenesis. By demonstrating that ADAR1 regulates the metabolic fitness of TNBC through desensitizing ferroptosis, we aim to leverage this metabolic vulnerability to inform basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC.
2025-01-13 | GSE286185 | GEO
Project description:The blossom of immunotherapy in melanoma highlights the need to delineate mechanisms of immune resistance. Recently, we have demonstrated that the RNA editing protein, adenosine deaminase acting on RNA-1 (ADAR1) is down-regulated during metastatic transition of melanoma, which enhances melanoma cell proliferation and tumorigenicity. Here we investigate the role of ADAR1 in melanoma immune resistance. Importantly, knockdown of ADAR1 in human melanoma cells induces resistance to tumor infiltrating lymphocytes in a cell contact-dependent mechanism. We show that ADAR1, in an editing-independent manner, regulates the biogenesis of miR-222 at the transcription level and thereby Intercellular Adhesion Molecule 1 (ICAM1) expression, which consequently affects melanoma immune resistance. ADAR1 thus has a novel, pivotal, role in cancer immune resistance. Corroborating with these results, the expression of miR-222 in melanoma tissue specimens was significantly higher in patients who had no clinical benefit from treatment with ipilimumab as compared to patients that responded clinically, suggesting that miR-222 could function as a biomarker for the prediction of response to ipilimumab. These results provide not only novel insights on melanoma immune resistance, but also pave the way to the development of innovative personalized tools to enable optimal drug selection and treatment. 13 formalin fixed paraffin embedded (FFPE) melanoma tissues were stained with hematoxilin and eosin for examination by an expert pathologist. Non-tumor tissue was removed. Total RNA was isolated using miRNeasy FFPE kit (Qiagen) according to the manufacture guidelines.
2015-12-31 | E-GEOD-67496 | biostudies-arrayexpress
Project description:Aberrant RNA-editing was observed in several human tumors, but its significance is mostly unknown. Here we show that ADAR1, a ubiquitous RNA-editing enzyme, is commonly lost in metastatic melanoma cells and specimens. Experimental ADAR1 silencing significantly alters melanoma cell morphology, facilitates proliferation and cell-cycle, and increases the tumorigenicity in-vivo. A series of ADAR1 truncation mutants establishes a novel RNA-editing-independent role for ADAR1 in controlling the nuclear and cytoplasmic processing steps of miRNA biogenesis. Altered expression of ADAR1-controled miRNAs accounts for the observed phenotype. We show that the oncogenic miR-17-5p endogenously regulates ADAR1 expression and that its genomic sequence is frequently amplified in melanoma to overexpress the mature miR-17-5p form. ADAR1 and miR-17-5p are ubiquitously expressed, suggesting the generality of this mechanism. Melanoma cell line expressing low ADAR1 levels (ADAR1-Knockdown) using shRNA technique were selected for RNA extraction and hybridization on Affymetrix microarrays. We sought to examine the alterations in the genes and microRNA expression profile in the manipulated cell system, due to ADAR1 possible involvement cancer development. To that end, we selected ADAR1-knockdown (ADAR1-KD) cells that demonstrated an enhanced aggressive phenotype both in vivo and in vitro as compared to the control cells (Control).
2012-08-31 | E-GEOD-31963 | biostudies-arrayexpress
Project description:Immune tolerance is an active state of unresponsiveness of the immune system to antigens (Ags) that have the potential to induce an immune response1. Such tolerance is beneficial in avoiding autoimmunity and rejection of organ transplants, but detrimental in cancer2. Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis3 and cross-presenting abilities4, resulting in T cell-mediated immunity5 or tolerance6-10. However, the mechanisms underlying the tolerogenic function of cDC1s remain largely unknown. Here, we show that the erythropoietin receptor (EpoR) acts as a critical switch that determines the tolerogenic state of cDC1s and the threshold of Ag-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance11,12, EpoR+ cDC1s induce donor-specific CD4+FoxP3+ regulatory T cells (Tregs), and conditional knockout of EpoR in cDC1s abrogates Ag-specific Treg induction, resulting in allograft rejection. In the steady state, EpoR+ migratory cDC1s control Ag-specific Treg induction in peripheral lymph nodes (LNs). In cancer, EpoR is expressed on both tumor Ag-carrying, tumor-infiltrating cDC1s, as well as migratory cDC1s in tumor-draining LNs (tdLNs). Loss of EpoR from cDC1s leads to tumor reduction by enhancing tumor Ag-specific CD8+ T cell priming and generating more precursor exhausted T cells13 in tdLNs, preserving CD8+ T cell precursor-like features and effector function, and reducing Tregs in the tumor. Thus, targeting EpoR on cDC1s to induce or inhibit immune tolerance should enable new ways to treat a variety of diseases.
2024-03-01 | GSE253056 | GEO
Project description:RNAseq analysis of cell lines with ADAR1-p150 and ADAR1-p110 knock-outs and primary human tissue samples (from GSE57353 and GSE99392 data sets) to identify sites of ADAR1 editing
2018-12-04 | GSE115127 | GEO