Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma
Michael Olvedy, … , Paulo De Sepulveda, Jean-Christophe Marine
Michael Olvedy, … , Paulo De Sepulveda, Jean-Christophe Marine
Published May 2, 2017
Citation Information: J Clin Invest. 2017;127(6):2310-2325. https://doi.org/10.1172/JCI91291.
View: Text | PDF
Research Article Genetics Oncology

Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma

Abstract

Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAFV600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer.

Authors

Michael Olvedy, Julie C. Tisserand, Flavie Luciani, Bram Boeckx, Jasper Wouters, Sophie Lopez, Florian Rambow, Sara Aibar, Bernard Thienpont, Jasmine Barra, Corinna Köhler, Enrico Radaelli, Sophie Tartare-Deckert, Stein Aerts, Patrice Dubreuil, Joost J. van den Oord, Diether Lambrechts, Paulo De Sepulveda, Jean-Christophe Marine

×

Figure 5

FES reexpression decreases cell proliferation in vitro and in vivo in a kinase-dependent manner.

Options: View larger image (or click on image) Download as PowerPoint
FES reexpression decreases cell proliferation in vitro and in vivo in a ...
(A) Western blot analysis of FES in MeWo cell line with overexpression of FES. Actin served as a loading control. (B) Clonogenic assay of MeWo cells with and without expression of exogenous FES. Error bars indicate mean ± SEM (n = 4 biological replicates per group). (C) Soft agar assay of MeWo cells with and without expression of exogenous FES. Error bars indicate mean ± SEM (n = 3 biological replicates per group). (D) Mice (n = 9) were injected with 1 × 106 MeWo cells to the left or MeWo cells expressing exogenous FES to the right side of the body. The tumor volume was measured every 3 to 4 days up to day 24. Error bars indicate mean ± SEM (n = 9 biological replicates per group). (E) Schematic indicating the location of the FES kinase-dead mutation. F-B, F-BAR domain. (F) Western blot analysis of doxycycline-induced expression of WT or mutant FES in MeWo cell line. Vinculin served as a loading control. (G) Clonogenic assay of MeWo cells expressing WT or mutant FES. Quantification of the assay measured as the percentage of area covered is shown in the graph on the right. Error bars indicate mean ± SEM (n = 3 biological replicates per group). Statistical significance was determined by unpaired 2-sided t test (B, G) and 2-way ANOVA (C, D).