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

Del Castillo Velasco-Herrera, Martin; van der Weyden, Louise; Nsengimana, Jeremie; Speak, Anneliese O.; Sjöberg, Marcela K.; Bishop, David Timothy; Jönsson, Göran LU ; Newton-Bishop, Julia and Adams, David J. (2018) In Molecular Oncology 12(2). p.239-255
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Comparative genomics, CRISPR, Melanoma, RNA-Seq
in
Molecular Oncology
volume
12
issue
2
pages
239 - 255
publisher
Elsevier
external identifiers
  • scopus:85040030469
ISSN
1574-7891
DOI
10.1002/1878-0261.12161
language
English
LU publication?
yes
id
9ec700fd-16e3-49ca-b677-ed12b4746c19
date added to LUP
2018-01-15 09:47:18
date last changed
2018-07-08 04:29:33
@article{9ec700fd-16e3-49ca-b677-ed12b4746c19,
  abstract     = {<p>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.</p>},
  author       = {Del Castillo Velasco-Herrera, Martin and van der Weyden, Louise and Nsengimana, Jeremie and Speak, Anneliese O. and Sjöberg, Marcela K. and Bishop, David Timothy and Jönsson, Göran and Newton-Bishop, Julia and Adams, David J.},
  issn         = {1574-7891},
  keyword      = {Comparative genomics,CRISPR,Melanoma,RNA-Seq},
  language     = {eng},
  number       = {2},
  pages        = {239--255},
  publisher    = {Elsevier},
  series       = {Molecular Oncology},
  title        = {Comparative genomics reveals that loss of lunatic fringe (LFNG) promotes melanoma metastasis},
  url          = {http://dx.doi.org/10.1002/1878-0261.12161},
  volume       = {12},
  year         = {2018},
}