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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

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.

Detaljer

Författare
  • Martin Del Castillo Velasco-Herrera
  • Louise van der Weyden
  • Jeremie Nsengimana
  • Anneliese O. Speak
  • Marcela K. Sjöberg
  • David Timothy Bishop
  • Göran Jönsson
  • Julia Newton-Bishop
  • David J. Adams
Enheter & grupper
Externa organisationer
  • Wellcome Trust Sanger Institute
  • St James's University Hospital
  • Pontifical Catholic University of Chile
  • Skåne University Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi

Nyckelord

Originalspråkengelska
Sidor (från-till)239-255
TidskriftMolecular Oncology
Volym12
Utgivningsnummer2
Tidigt onlinedatum2018 jan 7
StatusPublished - 2018 feb
PublikationskategoriForskning
Peer review utfördJa