Dichotomous roles of Arid5a augment the immunosuppressive microenvironment of mesenchymal malignant tumors
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PROVIDER: PRJNA670964 | ENA |
REPOSITORIES: ENA
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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
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
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Project description:Interleukin (IL-6) is a pleotropic cytokine with both tumor-promoting and -inhibitory effects on breast cancer growth. However, the mechanisms governing the outcome of IL-6 on cancer progression remain to be clarified. Our study unraveled a novel long noncoding RNA (lncRNA)-AU021063 downstream of IL-6 signaling. We found that IL-6 induced the expression of lncRNA-AU021063 predominantly in breast cancer compared to other cancer types. Mechanistically, IL-6 induced AT-rich interactive domain 5a (Arid5a) expression, which promotes the transcription of lncRNA-AU021063. In turn, lncRNA-AU021063 promotes breast cancer metastasis through stabilizing tribbles homolog 3 (Trib3) and activating Mek/Erk signaling pathway. Genetic ablation of either Arid5a, lncRNA-AU021063 or Trib3 abolished breast cancer metastasis in vitro and in vivo. Overall, our study highlights the importance of IL-6-Arid5a-lncRNA-AU021063 axis in regulating breast cancer invasiveness and metastasis, which may provide potential novel therapeutics for breast cancer.
2021-08-19 | GSE178249 | GEO
Project description:Interleukin (IL-6) is a pleotropic cytokine with both tumor-promoting and -inhibitory effects on breast cancer growth. However, the mechanisms governing the outcome of IL-6 on cancer progression remain to be clarified. Our study unraveled a novel long noncoding RNA (lncRNA)-AU021063 downstream of IL-6 signaling. We found that IL-6 induced the expression of lncRNA-AU021063 predominantly in breast cancer compared to other cancer types. Mechanistically, IL-6 induced AT-rich interactive domain 5a (Arid5a) expression, which promotes the transcription of lncRNA-AU021063. In turn, lncRNA-AU021063 promotes breast cancer metastasis through stabilizing tribbles homolog 3 (Trib3) and activating Mek/Erk signaling pathway. Genetic ablation of either Arid5a, lncRNA-AU021063 or Trib3 abolished breast cancer metastasis in vitro and in vivo. Overall, our study highlights the importance of IL-6-Arid5a-lncRNA-AU021063 axis in regulating breast cancer invasiveness and metastasis, which may provide potential novel therapeutics for breast cancer.
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Project description:Interleukin (IL-6) is a pleotropic cytokine with both tumor-promoting and -inhibitory effects on breast cancer growth. However, the mechanisms governing the outcome of IL-6 on cancer progression remain to be clarified. Our study unraveled a novel long noncoding RNA (lncRNA)-AU021063 downstream of IL-6 signaling. We found that IL-6 induced the expression of lncRNA-AU021063 predominantly in breast cancer compared to other cancer types. Mechanistically, IL-6 induced AT-rich interactive domain 5a (Arid5a) expression, which promotes the transcription of lncRNA-AU021063. In turn, lncRNA-AU021063 promotes breast cancer metastasis through stabilizing tribbles homolog 3 (Trib3) and activating Mek/Erk signaling pathway. Genetic ablation of either Arid5a, lncRNA-AU021063 or Trib3 abolished breast cancer metastasis in vitro and in vivo. Overall, our study highlights the importance of IL-6-Arid5a-lncRNA-AU021063 axis in regulating breast cancer invasiveness and metastasis, which may provide potential novel therapeutics for breast cancer.
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Project description:Hepatocellular carcinoma (HCC) involves a multistep pathological process in which heterogenous cells are evolved to shape an immunosuppressive microenvironment. Yet it remains largely unknown regarding the specific cell populations and their evolving routes essential for HCC development. Here, we created a rat model mimicking human HCC and generated a single-cell resolution atlas to HCC development. Specifically, we identified three populations of hepatic parenchymal cells during HCC progression, i.e., metabolic hepatocyte (HC Meta ), hepatic progenitor cell-like population with differentiation potential (HPC-like Diff ) and immunosuppressive malignant transformation subset (H-M Immu ). These three distinct subpopulations formed an oncogenic trajectory depicting a dynamic landscape of hepatocyte carcinogenesis, with signature genes reflecting the transition from HPC-like Diff to H-M Immu . Cross-species comparative analysis further revealed the H-M Immu subset to be highly conserved. Importantly, the H-M Immu (GPNMB + Gal-3 + ) cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 was found to be required for the generation of GPNMB + Gal-3 + H-M Immu cells and for their ability to form tumors. Enrichment of GPNMB + Gal-3 + H-M Immu subset was found to be associated with poor prognosis and higher rate of recurrence for HCC patients. Collectively, we unraveled the single-cell evolving mechanism of HCC and uncovered GPNMB + Gal-3 + H-M Immu cells as a major subset contributing to the immunosuppressive microenvironment and HCC malignance
2023-08-10 | GSE218561 | GEO
Project description:Hepatocellular carcinoma (HCC) involves a multistep pathological process in which heterogenous cells are evolved to shape an immunosuppressive microenvironment. Yet it remains largely unknown regarding the specific cell populations and their evolving routes essential for HCC development. Here, we created a rat model mimicking human HCC and generated a single-cell resolution atlas to HCC development. Specifically, we identified three populations of hepatic parenchymal cells during HCC progression, i.e., metabolic hepatocyte (HC Meta ), hepatic progenitor cell-like population with differentiation potential (HPC-like Diff ) and immunosuppressive malignant transformation subset (H-M Immu ). These three distinct subpopulations formed an oncogenic trajectory depicting a dynamic landscape of hepatocyte carcinogenesis, with signature genes reflecting the transition from HPC-like Diff to H-M Immu . Cross-species comparative analysis further revealed the H-M Immu subset to be highly conserved. Importantly, the H-M Immu (GPNMB + Gal-3 + ) cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 was found to be required for the generation of GPNMB + Gal-3 + H-M Immu cells and for their ability to form tumors. Enrichment of GPNMB + Gal-3 + H-M Immu subset was found to be associated with poor prognosis and higher rate of recurrence for HCC patients. Collectively, we unraveled the single-cell evolving mechanism of HCC and uncovered GPNMB + Gal-3 + H-M Immu cells as a major subset contributing to the immunosuppressive microenvironment and HCC malignance
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Project description:Tumors arise and grow despite anti-cancer immune responses. These responses can be stimulated by immunotherapies such as immune checkpoint inhibitors (e.g. anti-PD1 antibodies) and chimeric antigen receptors (CAR). Efficacy of these agents in solid tumors including colorectal cancers (CRC) is limited by immunosuppressive tumor microenvironment (TME) that prevents killing of malignant cells by cytotoxic T lymphocytes (CTL). Understanding the nature of TME-generated immunosuppression is of paramount importance. Here we report that TME elicited immunosuppression via eliminating activated CTL; this elimination required TME stress-induced downregulation of the IFNAR1 chain of type I interferon (IFN) receptor and attenuation of its signaling. Downregulation of IFNAR1 was observed in human colorectal cancers (CRC) and in mouse CRC models where it was required for efficient tumor development and progression. Stabilization of IFNAR1 on CTL improved their survival and increased anti- tumor activities of CAR T cells and PD1 inhibitors thereby providing a rationale for targeting IFNAR1 degradation for immunotherapies optimization. Two genotypes of mice were examined either 9 or 21 days post injection of MC38 colon cancer cells or MC38mRFP cells, respectively. 2-3 replicate mice were analyzed on separate arrays for each condition. 6 conditions in total were analyzed.
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