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

Although the expression of some long noncoding RNAs (lncRNAs), including MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), is predictive of metastasis, their impact and mechanism of action remain elusive. Here we use CRISPR activation (CRISPRa) to model MALAT1/Malat1 overexpression in patient-derived lung adenocarcinoma (LUAD) cell lines and in the autochthonous K-ras/p53 LUAD mouse model. The results indicate that Malat1 overexpression alone is sufficient to enable the progression of LUAD to metastatic disease. We show that overexpressed MALAT1/Malat1 enhances cell mobility and promotes the recruitment of pro-tumor macrophages to the tumor microenvironment through paracrine secretion of the CCL2/Ccl2 cytokine. We determine that Ccl2 upregulation results from an increase in global chromatin accessibility upon Malat1 overexpression. Importantly, 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. To examine the impact of Malat1 overexpression on chromatin accessibility in lung adenocarcinoma cells, we performed CRISPRa using luciferase (con) or Malat1 (mA2) targeting dRNAs in a cell line derived from KP mouse lung tumor. We then performed ATAC-seq in two biological replicate cell samples per treatment group.