Characterizing the roles of microRNA in metastatic lung adenocarcinoma and melanoma

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Watt, Kathleen
Cancer , Metastasis , MicroRNA
Cancer metastasis is the greatest ongoing obstacle to improving therapeutic efficacy and patient outcomes. Metastasis is a complex process reliant on phenotypic plasticity and dynamic changes in gene expression. MicroRNA (miRNA) are a class of small, non-coding RNAs that are post-transcriptional repressors of gene expression. Due to specificity for multiple targets and functional redundancy in the genome, miRNA fine-tune expression of gene-networks involved in virtually every cellular process. In cancer, dysregulated miRNAs can act as tumor suppressors, oncogenes, and are useful biomarkers. In this work, we examined the expression and function of miRNA in metastatic lung adenocarcinoma (LUAD) and cutaneous melanoma to gain insights into mechanisms of disease progression and metastasis. Due to numerous reports identifying miR-206 as a metastasis-suppressor in multiple cancers, we characterized the effects of ectopic expression in LUAD, finding that miR-206 mediated suppression of tumor growth and metastasis through broad disruption of TGF-β signaling. However, the highly muscle-specific expression patterns of miR-206 imply that this miRNA plays no physiological role in preventing LUAD. To explore the reasons why miR-206 is widely identified in cancers outside of muscle, we analyzed miRNA expression in primary and metastatic melanoma tumors in The Cancer Genome Atlas cohort, as well as melanoma and stromal cell lines. We determined that miR-206 and several other highly-studied metastasis-suppressor miRNAs were likely identified due to enrichment in stromal cells, highlighting the need to consider cell-type composition in tissue-level miRNA data. Through characterizing miRNA expression in melanoma, we identified a novel subset harboring expression of the chromosome 19 miRNA cluster (C19MC). C19MC was associated with overexpression of cancer/testis antigens, altered global DNA methylation profiles, and enrichment of embryonic gene expression patterns consistent with dedifferentiation. Furthermore, we identified five melanoma cell lines with endogenous C19MC expression and established tumor xenograft models to compare tumor growth and metastasis potential in vivo. These models will facilitate further functional studies of C19MC in melanoma and identification of new therapeutic vulnerabilities. Overall, the findings presented here provide insights into the functional roles of miRNAs in metastatic cancers, highlighting challenges in research methodology, and the potential applications of this research in cancer.
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