| Autor: |
Martinez-Terroba, Elena, Plasek-Hegde, Leah M., Chiotakakos, Ioannis, Li, Vincent, de Miguel, Fernando J., Robles-Oteiza, Camila, Tyagi, Antariksh, Politi, Katerina, Zamudio, Jesse R., Dimitrova, Nadya |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 96, p1-16, 16p |
| Abstrakt: |
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. Editor's summary: The long noncoding RNA (lncRNA) MALAT1 is overexpressed in many tumor types, and expression is associated with metastasis. Martinez-Terroba et al. used CRISPR activation to investigate how MALAT1/Malat1 promotes metastasis in human and murine lung adenocarcinoma (LUAD). Overexpression of Malat1 resulted in altered global chromatin accessibility and increased transcription of Ccl2 in murine tumor cells. Ccl2 secretion promoted recruitment of protumorigenic macrophages and metastasis, which could be rescued by blockade of Ccl2 or by macrophage depletion. These findings indicate that MALAT1/Malat1 overexpression induces reprogramming of the tumor microenvironment in LUAD to drive metastasis. —Hannah Isles [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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