In Vivo miRNA Decoy Screen Reveals miR-124a as a Suppressor of Melanoma Metastasis

Abstract

Melanoma is a highly prevalent cancer with an increasing incidence worldwide and high metastatic potential. Brain metastasis is a major complication of the disease, as more than 50% of metastatic melanoma patients eventually develop intracranial disease. MicroRNAs (miRNAs) have been found to play an important role in the tumorigenicity of different cancers and have potential as markers of disease outcome. Identification of relevant miRNAs has generally stemmed from miRNA profiling studies of cells or tissues, but these approaches may have missed miRNAs with relevant functions that are expressed in subfractions of cancer cells. We performed an unbiased in vivo screen to identify miRNAs with potential functions as metastasis suppressors using a lentiviral library of miRNA decoys. Notably, we found that a significant fraction of melanomas that metastasized to the brain carried a decoy for miR-124a, a miRNA that is highly expressed in the brain/neurons. Additional loss- and gain-of-function in vivo validation studies confirmed miR-124a as a suppressor of melanoma metastasis and particularly of brain metastasis. miR-124a overexpression did not inhibit tumor growth in vivo, underscoring that miR-124a specifically controls processes required for melanoma metastatic growth, such as seeding and growth post-extravasation. Finally, we provide proof of principle of this miRNA as a promising therapeutic agent by showing its ability to impair metastatic growth of melanoma cells seeded in distal organs. Our efforts shed light on miR-124a as an antimetastatic agent, which could be leveraged therapeutically to impair metastatic growth and improve patient survival.

Epigenomic analysis of formalin-fixed paraffin-embedded samples by CUT&Tag

“…We found that FFPE-CUTAC sensitively detects cCRE clusters spanning microRNA loci that gain RNAPII in the RELA fusion-driven tumor. Strikingly, the 10 most down-regulated cCREs corresponded to two unlinked loci for the mouse Mir124a microRNA, which was previously described as a neuronal differentiation factor 61 , a tumor suppressor in brain 62 and a unique human biomarker for H. pylori infection and gastric cancer risk 53 . Although Mir124a is one of the most abundantly expressed microRNAs in the central nervous system 61 , we found that it is present at only average levels in RNA-seq data.…”

Insights into the Molecular Mechanisms Mediating Extravasation in Brain Metastasis of Breast Cancer, Melanoma, and Lung Cancer

“…Similarly, microRNA-146a was shown to suppress melanoma metastatic activity in brain metastasis [ 122 ], while miR-124a, a miRNA that is highly expressed in the brain was shown as a suppressor of melanoma metastasis in vivo, particularly of brain metastasis. A significant fraction of melanomas that metastasized to the brain was found to carry a decoy of miR-124a [ 123 ]. MicroRNA-23a was shown to inhibit melanoma cell proliferation, migration, and invasion in mice through a negative feedback regulation of sdcbp and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway [ 124 ].…”