Overexpression of <i>Malat1</i> drives metastasis through inflammatory reprogramming of the tumor microenvironment

Abstract

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