Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma
A partir d'échantillons tumoraux prélevés sur 43 patients atteints d'un mélanome muqueux, puis à l'aide d'un modèle animal (poisson-zèbre), cette étude met en évidence des mécanismes par lesquels le gène SPRED1 exerce une fonction de suppresseur de tumeurs
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.