The chromosome-19 microRNA cluster promotes a dedifferentiated, metastatic phenotype in malignant melanoma

Abstract

Cutaneous melanoma is an aggressive form of skin cancer that often progresses to metastatic and fatal disease. Despite recent advances in targeted therapies and immunotherapies, few patients with metastases survive. This highlights the need for therapies that block metastasis by better defining the molecular mechanisms. Recently, we profiled microRNA (miRNA) expression in the skin cutaneous melanoma (SKCM) cohort of the cancer genome atlas and discovered amplification of the Chromosome-19 miRNA cluster (C19MC) in approximately 10% of SKCM tumors. C19MC expression is normally restricted to a few tissues, and it regulates placental trophoblast migration and differentiation. Recently, C19MC was identified as an oncogenic driver in some embryonal brain cancers. However, the role of C19MC expression in melanoma has not been reported and we hypothesized that C19MC activation may promote a dedifferentiated, metastatic melanoma phenotype. To test this hypothesis, we induced C19MC expression in A375 melanoma cells using a CRISPR/dCas9-based activation system and validated that several C19MC miRNAs were upregulated compared to isogenic controls. C19MC activation in A375 cells caused reduced cell growth, migration, and invasion in vitro. In human A375 melanoma tumor xenograft assays, we found that C19MC activation reduced primary tumor growth with increased spontaneous liver metastases. C19MC expression also increased liver metastases in experimental metastasis assays. Profiling gene and protein expression changes revealed C19MC+ samples had increased stem cell features and decreased CDK2 expression, which may explain altered growth and metastasis phenotypes. While future experiments are required to corroborate underlying mechanisms, the present study contributes new knowledge that will ultimately help to optimize treatments for this subset of melanoma.