Cancer cell metabolism is a targetable vulnerability; however, a precise understanding of metabolic heterogeneity is required. Inactivating mutations in BRCA1-associated protein 1 (BAP1) are associated with metastasis in uveal melanoma (UM), the deadliest adult eye cancer. BAP1 functions in UM remain unclear. UM patient sample analysis divided BAP1 mutant UM tumors into two subgroups based on oxidative phosphorylation (OXPHOS) gene expression suggesting metabolic heterogeneity. Consistent with patient data, transcriptomic analysis of BAP1 mutant UM cell lines also showed OXPHOShigh or OXPHOSlow subgroups. Integrated RNA sequencing, metabolomics, and molecular analyses showed that OXPHOShigh BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOSlow BAP1 mutant UM cells employ fatty acid oxidation. Furthermore, the two subgroups responded to different classes of metabolic suppressors. Our findings indicate that targeting cancer metabolism is a promising therapeutic option for BAP1 mutant UM; however, tailored approaches may be required due to metabolic heterogeneities.
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Bulk RNA-Sequencing data have been deposited to the Gene Expression Omnibus (GEO) database with accession code GSE149920.
Computational analyses were done using publicly-available software and R packages.
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We thank Dr. Sergio Roman-Roman (Uveal Melanoma Translational Group, Department of Translational Research, Institute Curie, PSL Research University, Paris, France) for cell lines. We thank Dr. Michele Carbone (University of Hawaii Cancer Center, Honolulu, HI, USA) for BAP1 cDNA. This work was supported by a Melanoma Research Alliance team science award (#559058) to AEA and JWH. Further support was from National Institutes of Health (NIH)/National Cancer Institute (NCI), R01 CA196278 and R01 CA253977 to AEA, P50CA174523 to DWS and fellowships from the National Cancer Center and American Association for Cancer Research (AACR)/Ocular Melanoma Foundation (OMF) awarded to AH and VC. This work was also supported by grant from NCI P01 CA114046. The Wistar Proteomics and Metabolomics Facility was supported by P30CA010815 and S10OD023586.
Conflict of interest
AEA reports receiving a commercial research grant from Pfizer Inc. (2013–2017) and has ownership interest in patent number 9880150. No potential conflicts of interest are disclosed by the other authors. JWH is the inventor of intellectual property related to prognostic testing for uveal melanoma. He is a paid consultant for Castle Biosciences, licensee of this intellectual property, and he receives royalties from its commercialization.
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Han, A., Purwin, T.J., Bechtel, N. et al. BAP1 mutant uveal melanoma is stratified by metabolic phenotypes with distinct vulnerability to metabolic inhibitors. Oncogene 40, 618–632 (2021). https://doi.org/10.1038/s41388-020-01554-y