Malat1 的过表达通过肿瘤微环境的炎症重编程驱动转移。

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2024-06-14 DOI:10.1126/sciimmunol.adh5462

Elena Martinez-Terroba, Leah M. Plasek-Hegde, Ioannis Chiotakakos, Vincent Li, Fernando J. de Miguel, Camila Robles-Oteiza, Antariksh Tyagi, Katerina Politi, Jesse R. Zamudio, Nadya Dimitrova

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引用次数: 0

摘要

在许多肿瘤类型中，长非编码 RNA（lncRNA）转移相关肺腺癌转录本 1（MALAT1）的表达与肿瘤的进展和转移有关。然而，MALAT1 促进转移性疾病的影响和作用机制仍然难以捉摸。在这里，我们利用CRISPR激活（CRISPRa）技术在源自患者的肺腺癌（LUAD）细胞系和自体K-ras/p53 LUAD小鼠模型中过表达MALAT1/Malat1。Malat1 的过表达足以促进 LUAD 在小鼠中发展为转移性疾病。MALAT1/Malat1的过表达增强了细胞的流动性，并通过CCL2/Ccl2的旁分泌促进了肿瘤微环境中原肿瘤性巨噬细胞的招募。Ccl2的上调是Malat1过表达后全局染色质可及性增加的结果。巨噬细胞耗竭和Ccl2阻断可抵消Malat1过表达的影响。这些数据证明，单个lncRNA可通过重编程肿瘤微环境来驱动LUAD转移。

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Overexpression of Malat1 drives metastasis through inflammatory reprogramming of the tumor microenvironment

Expression of the long noncoding RNA (lncRNA) metastasis–associated lung adenocarcinoma transcript 1 (MALAT1) correlates with tumor progression and metastasis in many tumor types. However, the impact and mechanism of action by which MALAT1 promotes metastatic disease remain elusive. Here, we used CRISPR activation (CRISPRa) to overexpress MALAT1/Malat1 in patient-derived lung adenocarcinoma (LUAD) cell lines and in the autochthonous K-ras/p53 LUAD mouse model. Malat1 overexpression was sufficient to promote the progression of LUAD to metastatic disease in mice. Overexpression of MALAT1/Malat1 enhanced cell mobility and promoted the recruitment of protumorigenic macrophages to the tumor microenvironment through paracrine secretion of CCL2/Ccl2. Ccl2 up-regulation was the result of increased global chromatin accessibility upon Malat1 overexpression. Macrophage depletion and Ccl2 blockade counteracted the effects of Malat1 overexpression. These data demonstrate that a single lncRNA can drive LUAD metastasis through reprogramming of the tumor microenvironment.

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.