OverexpressedMalat1Drives Metastasis through Inflammatory Reprogramming of Lung Adenocarcinoma Microenvironment

Abstract

AbstractMetastasis is the main cause of cancer deaths but the molecular events leading to metastatic dissemination remain incompletely understood. Despite reports linking aberrant expression of long noncoding RNAs (lncRNAs) with increased metastatic incidence, in vivoevidence establishing driver roles for lncRNAs in metastatic progression is lacking. Here, we report that overexpression of the metastasis-associated lncRNAMalat1(metastasis-associated lung adenocarcinoma transcript 1) in the autochthonous K-ras/p53 mouse model of lung adenocarcinoma (LUAD) is sufficient to drive cancer progression and metastatic dissemination. We show that increased expression of endogenousMalat1RNA cooperates with p53 loss to promote widespread LUAD progression to a poorly differentiated, invasive, and metastatic disease. Mechanistically, we observe thatMalat1overexpression leads to the inappropriate transcription and paracrine secretion of the inflammatory cytokine, Ccl2, to augment the mobility of tumor and stromal cellsin vitroand to trigger inflammatory responses in the tumor microenvironmentin vivo. Notably, Ccl2 blockade fully reverses cellular and organismal phenotypes ofMalat1overexpression. We propose thatMalat1overexpression in advanced tumors activates Ccl2 signaling to reprogram the tumor microenvironment to an inflammatory and pro-metastatic state.