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

Sci Immunol. 2024 Jun 14;9(96):eadh5462. doi: 10.1126/sciimmunol.adh5462. Epub 2024 Jun 14.

Abstract

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.

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / immunology
  • Adenocarcinoma of Lung* / pathology
  • Animals
  • Cell Line, Tumor
  • Chemokine CCL2* / genetics
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / pathology
  • Lung Neoplasms* / secondary
  • Macrophages / immunology
  • Mice
  • Neoplasm Metastasis*
  • RNA, Long Noncoding* / genetics
  • Tumor Microenvironment* / immunology

Substances

  • RNA, Long Noncoding
  • MALAT1 long non-coding RNA, human
  • Chemokine CCL2
  • Malat1 long non-coding RNA, mouse
  • CCL2 protein, human
  • Ccl2 protein, mouse