Comparative genomics reveals that loss of lunatic fringe (LFNG) promotes melanoma metastasis

Metastasis is the leading cause of death of patients with advanced melanoma, yet the somatic alterations that aid tumour cell dissemination and colonization are poorly understood. Here we deploy comparative genomics to identify and validate clinically relevant drivers of melanoma metastasis. To do this we identified a set of 976 genes whose expression level was associated with a poor outcome in patients from two large melanoma cohorts. We next characterised the genomes and transcriptomes of mouse melanoma cell lines defined as weakly metastatic and their highly metastatic derivatives. By comparing expression data between species we identified Lunatic Fringe (LFNG), amongst 28 genes whose expression level is predictive of poor prognosis, and whose altered expression is associated with a pro-metastatic phenotype in mouse melanoma cells. CRISPR/Cas9 mediated knockout of Lfng dramatically enhanced the capability of weakly metastatic melanoma cells to metastasize in vivo, a phenotype that could be rescued with the Lfng cDNA. Notably, genomic alterations disrupting LFNG are found exclusively in human metastatic melanomas sequenced as part of The Cancer Genome Atlas. Using comparative genomics we show that LFNG expression plays a functional role in regulating melanoma metastasis.