ZFIN ID: ZDB-PUB-181103-1
Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma.
Ablain, J., Xu, M., Rothschild, H., Jordan, R.C., Mito, J.K., Daniels, B.H., Bell, C.F., Joseph, N.M., Wu, H., Bastian, B.C., Zon, L.I., Yeh, I.
Date: 2018
Source: Science (New York, N.Y.)   362(6418): 1055-1060 (Journal)
Registered Authors: Zon, Leonard I.
Keywords: none
MeSH Terms:
  • Animals
  • Drug Resistance, Neoplasm/genetics
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Genes, Neoplasm*
  • Genomics
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics*
  • Melanoma/genetics*
  • Melanoma/pathology
  • Melanoma, Experimental/genetics
  • Membrane Proteins/genetics*
  • Mitogen-Activated Protein Kinases/genetics
  • Mitogen-Activated Protein Kinases/metabolism*
  • Mucous Membrane/enzymology
  • Mucous Membrane/pathology
  • Proto-Oncogene Proteins c-kit/genetics
  • Signal Transduction
  • Skin Neoplasms/genetics*
  • Skin Neoplasms/pathology
  • Zebrafish
PubMed: 30385465 Full text @ Science
Melanomas originating from mucosal surfaces have low mutation burden, genomic instability, and poor prognosis. To identify potential driver genes, we sequenced hundreds of cancer-related genes in 43 human mucosal melanomas, cataloguing point mutations, amplifications and deletions. The SPRED1 gene, which encodes a negative regulator of MAPK signaling, was inactivated in 37% of the tumors. Four distinct genotypes were associated with SPRED1 loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, we found that SPRED1 functions as a tumor suppressor, particularly in the context of KIT mutations. SPRED1 knockdown caused MAPK activation, increased cell proliferation and conferred resistance to drugs inhibiting KIT tyrosine kinase activity. These findings provide a rationale for MAPK inhibition in SPRED1-deficient melanomas and introduce a zebrafish modeling approach that can be used more generally to dissect genetic interactions in cancer.