Open AccessComparative genomics reveals that loss of lunatic fringe ( LFNG ) promotes melanoma metastasis
Author(s) -
Del Castillo VelascoHerrera Martin,
Weyden Louise,
Nsengimana Jeremie,
Speak Anneliese O.,
Sjöberg Marcela K.,
Bishop David Timothy,
Jönsson Göran,
NewtonBishop Julia,
Adams David J.
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12161
Subject(s) - melanoma , biology , cancer research , metastasis , transcriptome , carcinogenesis , phenotype , functional genomics , gene expression profiling , crispr , genomics , comparative genomics , genome , cancer , gene expression , gene , genetics
Metastasis is the leading cause of death in patients with advanced melanoma, yet the somatic alterations that aid tumour cell dissemination and colonisation 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. Next, we 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) , among 28 genes whose expression level is predictive of poor prognosis and whose altered expression is associated with a prometastatic phenotype in mouse melanoma cells. CRISPR/Cas9‐mediated knockout of Lfng dramatically enhanced the capability of weakly metastatic melanoma cells to metastasise 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.