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Published on: January 7, 2019
Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma
Michael Olvedy1,2, Julie C Tisserand3, Flavie Luciani1,2
1Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
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.
Insights
This study identifies FES as a novel melanoma driver gene. Its decreased expression correlates with poor survival, and its loss accelerates tumor growth in mouse models, highlighting its therapeutic potential.
Area of Science:
- Oncogenomics
- Cancer Biology
- Translational Medicine
Background:
- Identifying oncogenic drivers is crucial for advancing precision cancer medicine.
- BRAFV600E and NRASQ61K mutations are common drivers in melanoma.
Purpose of the Study:
- To comprehensively analyze the genomic landscape of BRAFV600E- and NRASQ61K-driven melanoma mouse models.
- To integrate mouse model data with human clinical data to identify novel melanoma drivers.
- To functionally validate the role of identified drivers in melanoma progression.
Main Methods:
- Somatic genomic landscape analysis of mouse melanoma models.
- Integration of multi-omics data (genomic, epigenomic, transcriptomic) from mouse models and human samples.
- Functional validation using engineered gene deletion in mouse models.
Main Results:
- Confirmed known melanoma drivers like PTEN, CDKN2A, and LKB1.
- Identified FES tyrosine kinase as a novel putative melanoma driver.
- Found decreased FES expression in over 30% of human melanomas, correlating with poor survival.
- Engineered Fes deletion accelerated tumor progression in a BRAFV600E mouse model.
Conclusions:
- FES is implicated as a driver of melanoma progression.
- Cross-species oncogenomic approaches combined with mouse modeling can uncover clinically relevant cancer drivers.
- FES represents a potential therapeutic target for melanoma treatment.
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