Although great advances have been made in combatting cancer, particularly at its early stages, metastasis remains a formidable and frequently fatal challenge. It has become evident that non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), are components of molecular networks regulating metastasis. Some lncRNAs are known to have opposing functions to their genomic locus; for instance, opposite phenotypes have been reported from the lncRNA Haunt gene deletion and insertional inactivation, and interestingly, the Haunt gene deletion effect was due to the loss of the genomic DNA but not the loss of Haunt RNA. Thus, a major challenge in lncRNA research is whether phenotypes resulting from deleting or inactivating a lncRNA gene can be unequivocally attributed either to the loss of the lncRNA per se or to the loss of overlapping regulatory elements. MALAT1 (metastasis associated lung adenocarcinoma transcript 1) is among the most abundant and conserved lncRNAs in normal tissues, and has previously been described as a metastasis promoter. However, there is no evidence that the previously reported Malat1 gene deletion (which led to upregulation of multiple Malat1's adjacent genes) or antisense RNA (which has never been validated by rescue experiments or by MALAT1 knockout cells) effect was specific to Malat1 lncRNA loss. Unexpectedly, using a transcriptional terminator insertion strategy, we found that disrupting the Malat1 gene without altering the expression of its adjacent genes in a transgenic mouse model of breast cancer drastically promoted lung metastasis, and importantly, this phenotype was completely reversed by genetic add-back of Malat1. Moreover, CRISPR-Cas9- mediated knockout of MALAT1 in human breast cancer cells induced their metastatic ability, which was reversed by Malat1 re-expression. Conversely, overexpression of Malat1 suppressed breast cancer metastasis in both transgenic mice and xenograft models. Mechanistically, we used a recently developed chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) approach to identify TEAD family members as binding proteins for MALAT1 at the endogenous level from primary mammary tumor tissues, and discovered that MALAT1 binds, sequesters, and inactivates the pro-metastatic transcription factor TEAD. We also found an inverse correlation of MALAT1 levels with breast cancer progression and metastasis. Based on these important findings, we propose to comprehensively characterize the loss-of-function and gain-of-function effects of MALAT1 in breast cancer metastasis, using genetically engineered mouse models, transplantation models, syngeneic models, xenograft models, and CRISPR-Cas9 genome editing approaches (Specific Aim 1); we will also elucidate the mechanism by which MALAT1 regulates metastasis (Specific Aim 2). This project will lead to a major revision of the current model for a highly abundant and conserved lncRNA, and will profoundly advance the understanding of lncRNA's functions and mechanisms of action in tumor metastasis.

Public Health Relevance

Questions have been raised as to whether phenotypes resulting from deleting or inactivating a long non-coding RNA (lncRNA) gene can be unequivocally attributed either to the loss of the lncRNA per se or to the loss of overlapping regulatory elements. Unexpectedly, we found drastic metastasis induction in a mouse model of breast cancer upon insertional inactivation of the lncRNA Malat1, which was validated to be specific to Malat1 lncRNA loss by the genetic rescue approach. The goal of this project is to provide important new insights into the role and mechanism of action of a highly abundant and conserved lncRNA in tumor metastasis, which has significant clinical implications in regards to the biomarkers and therapeutic targets for metastatic cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Ault, Grace S
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University of Texas MD Anderson Cancer Center
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Kim, Jongchan; Piao, Hai-Long; Kim, Beom-Jun et al. (2018) Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet 50:1705-1715
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