Abstract 1540: Accumulation of the long noncoding RNA Malat1 is a central driver and therapeutic target in metastatic lung cancer

Abstract

Abstract The identification and functional characterization of long noncoding RNAs (lncRNAs) have suggested a potential source of unexplored cancer therapy targets. The metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was initially identified as a transcript significantly overexpressed in metastatic lung adenocarcinoma (LUAD) and strongly correlated with poor patient outcomes. Despite decades of effort to elucidate Malat1 functions and mechanisms of action in cancer, two key questions have remained unresolved: 1) Is Malat1 overexpression a driver of LUAD progression? and 2) What is the mechanism by which Malat1 overexpression promotes LUAD progression? We utilized CRISPR activation to model Malat1 overexpression in patient-derived LUAD cell lines and in the autochthonous KrasG12D/p53-deficient murine model of LUAD. We observed that Malat1 overexpression cooperates with p53 loss to promote LUAD progression and metastatic dissemination in vivo. Compared to controls, Malat1-overexpressing KrasG12D/p53-deficient tumors appeared poorly differentiated and were characterized by excessive stromal infiltration. Single-cell RNA sequencing of dissociated tumors revealed that Malat1 overexpression triggers pleiotropic immune and stromal responses that favor a metastasis-permissive tumor microenvironment through the secretion of cytokines and metalloproteinases and the recruitment of CAFs and tumor-associated macrophages. Consistent with the in vivo findings, we observed that Malat1 overexpression in vitro does not affect the proliferation but promotes the migration of tumor cells and cancer-associated fibroblasts (CAFs) through secreted factors, including inflammatory cytokines. Importantly, targeting the stabilizing ENE domain of overexpressed Malat1 by two independent approaches in vitro - direct mutagenesis and non-degrading antisense oligonucleotide (ASO) - led to Malat1 destabilization and rescued the increased cellular migration. Similarly, cytokine-targeted blocking antibodies reversed the effects of Malat1 overexpression. In sum, our results represent the first successful efforts to model the increased Malat1 levels observed in human LUAD and to dissect the pro-metastatic molecular consequences of overexpressed Malat1. Our findings indicate that Malat1 is both necessary and sufficient to rewire metastatic pathways and our preliminary data support further efforts to therapeutically target Malat1 and its downstream mediators in metastatic LUAD. Citation Format: Elena Martínez-Terroba, Fernando J. de Miguel, Camila Robles-Oteiza, Katerina Politi, Nadya Dimitrova. Accumulation of the long noncoding RNA Malat1 is a central driver and therapeutic target in metastatic lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1540.