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Dichotomous roles of Arid5a augment the immunosuppressive microenvironment of mesenchymal malignant tumors

ABSTRACT: Dichotomous roles of Arid5a augment the immunosuppressive microenvironment of mesenchymal malignant tumors

PROVIDER: PRJNA670964 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12885017.fastq.gz	Fastqsanger.gz
	SRR12885018.fastq.gz	Fastqsanger.gz
	SRR12885019.fastq.gz	Fastqsanger.gz
	SRR12885020.fastq.gz	Fastqsanger.gz
	SRR12885021.fastq.gz	Fastqsanger.gz

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Dichotomous roles of Arid5a augment the immunosuppressive microenvironment of mesenchymal malignant tumors

Project description:Although mesenchymal subtypes of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are known as “immunologically cold” tumors, the molecular link between tumor immune evasiveness and mesenchymal phenotype remains largely unknown. Here, we show that AT-rich interaction domain-containing protein 5a (Arid5a), an RNA-binding protein, is involved in immune evasion in PDAC and CRC mouse models. Mass cytometry demonstrated that in tumors from Arid5a-deficient cells, the infiltration of granulocytic myeloid-derived suppressor cells and regulatory T cells is suppressed, but cytotoxic T-lymphocyte recruitment is enhanced. Mechanistically, Arid5a augmented Ido1 and Ccl2 expression by stabilizing these mRNAs in the PDAC model, but not Ido1 in the CRC model. Furthermore, Arid5a expression was substantially increased in mesenchymal subtypes of PDAC and CRC, mediated by ZEB1, and Arid5a promoted TGF-b-induced and IL6-induced epithelial-mesenchymal transition and acquisition of invasiveness in PDAC model cells. Thus, our findings demonstrate that Arid5a is a promising target for immunotolerant malignant tumors.

2021-04-07 | GSE159967 | GEO

Arid5a directs autoimmune inflammation through an IL-17 signaling pathway [mouse]

Project description:Using Arid5a deficient mice to study the role of the RNA-binding protein Arid5a in models of autoimmunity, namely autoimmune glomerulonephritis

2024-07-15 | GSE269729 | GEO

Arid5a directs autoimmune inflammation through an IL-17 signaling pathway [human]

Project description:Using Arid5a deficient mice to study the role of the RNA-binding protein Arid5a in models of autoimmunity, namely autoimmune glomerulonephritis

2024-07-15 | GSE269728 | GEO

Transcriptome-wide mapping of RNA:protein interactions of Arid5a in mouse P19 cells.

Project description:We performed Arid5a iCLIP2 in P19 cells transiently expressing GFP-tagged Arid5a.

2024-08-01 | GSE254818 | GEO

Modulation of the DNA/RNA Binding Protein ARID5A Regulates Microglial Activation and Response

Project description:RNA binding proteins (RBPs) shape cellular function in health and disease. However, the function of RBPs expressed specifically in the central nervous system (CNS) remain uncharacterized. Within the CNS, we identify ARID5A as a microglial-specific RBP and integrate multi-omics analyses of ARID5A's RNA, DNA, and protein interactions to uncover its RNA-mediated regulation of microglial functions. We show ARID5A regulates the splicing and translation of its RNA targets, many of which are integral to microglial functions. We find ARID5A modulates cytokine secretion, lysosome activity, and iron accumulation, as well as ferroptosis sensitivity in microglia and co-cultured neurons. We illustrate the neuroprotective potential of ARID5A modulation, in which knockdown restored dysregulated functions in TREM2 mutant microglia. Our results highlight the potential of leveraging ARID5A-RNA interactions to restore dysregulated pathways in neurodegeneration.

2026-04-17 | GSE290755 | GEO

Modulation of the DNA/RNA Binding Protein ARID5A Regulates Microglial Activation and Response [cutnrun]

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Modulation of the DNA/RNA Binding Protein ARID5A Regulates Microglial Activation and Response [eclip]

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Modulation of the DNA/RNA Binding Protein ARID5A Regulates Microglial Activation and Response [RIP-Seq]

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The disordered extensions of the Arid5a core ARID domain modulate its DNA- and RNA-binding propensities

Project description:ARID (AT-rich interacting domain) proteins are a heterogeneous family of DNA-binding proteins involved in transcriptional regulation. No precise DNA-binding preferences have yet been defined for the aberrant member Arid5a. In addition, the protein binds to mRNA motifs for transcript stabilisation, presumably through the DNA-binding ARID domain. Here we first provide an unbiased definition of RNA motifs and a clear breakdown of nucleic acid binding by the ARID domain. An RNA Bind-n-Seq (RBNS) experiment was performed to find a consensus motif of the Arid5a domain. It reveals a preference for an unexpected CAGGCAG consensus motif, accompanied by a general preference for AU-rich motifs.

2024-03-21 | GSE256029 | GEO

Immunosuppressive myeloid signaling and distinct malignant cell states in pancreatic neuroendocrine tumors revealed by single-nucleus RNA-seq

Project description:Pancreatic neuroendocrine tumors (PNET) are rare and heterogeneous neoplasms with increasing incidence worldwide. Currently, there is no clinically-relevant molecular framework for risk-stratifying patients with PNET. In this study, we used single-nucleus RNA-sequencing to uncover the spectrum of malignant cell states and interactions within the tumor microenvironment. We uncovered a gene expression program enriched in neural/synaptic signaling genes associated with aggressive clinical behavior, altered telomeres, and broad chromosomal loss of heterozygosity. Moreover, it is associated with worse overall survival in independent cohorts. Another novel malignant cell state was enriched for VEGF-signaling and found to interact with macrophages via glutamate, promoting an immunosuppressive phenotype in macrophages and a more invasive phenotype in malignant cells. This study provides insight into the heterogeneity of malignant cells in PNET, and these diverse cell states and intercellular interactions that may be further explored for prognostication and therapeutic targeting.

2026-02-18 | GSE301075 | GEO

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