Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma
| Autor: | Julien Ablain, Leonard I. Zon, Nancy M. Joseph, Jeffrey K. Mito, Iwei Yeh, Caitlin F. Bell, Harriet Rothschild, Brianne H. Daniels, Mengshu Xu, Richard C.K. Jordan, Boris C. Bastian, Hong Wu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Genome instability Skin Neoplasms Melanoma Experimental Drug Resistance medicine.disease_cause 2.1 Biological and endogenous factors Aetiology Zebrafish Melanoma Cancer Mutation Gene knockdown Multidisciplinary Intracellular Signaling Peptides and Proteins Adaptor Proteins Genomics Gene Expression Regulation Neoplastic Proto-Oncogene Proteins c-kit Gene Knockdown Techniques Mitogen-Activated Protein Kinases Tyrosine kinase Signal Transduction Biotechnology General Science & Technology Biology Article 03 medical and health sciences Experimental medicine Genetics Animals Humans Adaptor Proteins Signal Transducing Neoplastic Mucous Membrane Point mutation Human Genome Signal Transducing Membrane Proteins medicine.disease biology.organism_classification 030104 developmental biology Gene Expression Regulation Genes Drug Resistance Neoplasm Cancer research Neoplasm Gene Deletion Genes Neoplasm |
| Zdroj: | Science (New York, N.Y.), vol 362, iss 6418 |
| Popis: | 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, cataloging point mutations, amplifications, and deletions. The SPRED1 gene, which encodes a negative regulator of mitogen-activated protein kinase (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. |
| Databáze: | OpenAIRE |
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