PUBLICATION
Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma.
- Authors
- 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.
- ID
- ZDB-PUB-181103-1
- 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
Citation
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. (2018) Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma.. Science (New York, N.Y.). 362(6418):1055-1060.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping