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BAP1 mutant uveal melanoma is stratified by metabolic phenotypes with distinct vulnerability to metabolic inhibitors

A Correction to this article was published on 28 January 2021

This article has been updated

Abstract

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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Fig. 1: BAP1 mutant UM samples are divided into two distinct metabolic subpopulations based on OXPHOS gene set.
Fig. 2: BAP1 status alters the metabolic pathways in UM cells.
Fig. 3: OXPHOShigh BAP1 mutant phenotype is linked to increased glycolytic-nucleotide biosynthetic pathway.
Fig. 4: OXPHOSlow BAP1 mutant phenotype is associated with an elevated FA oxidation pathway.
Fig. 5: The two metabolic phenotypes respond differently to metabolic stress.
Fig. 6: Nucleotide and FA metabolism gene expressions separate BAP1 mutant samples into two distinct subgroups.
Fig. 7: Two distinct metabolic phenotypes in BAP1 mutant UM.

Data availability

Bulk RNA-Sequencing data have been deposited to the Gene Expression Omnibus (GEO) database with accession code GSE149920.

Code availability

Computational analyses were done using publicly-available software and R packages.

Change history

  • 14 January 2021

    The original published version was the given name from J. William Harbour incorrect tagged. It was given as J. (given name) William Harbour (family name) it was corrected to J. William (given name) Harbour (family name).

  • 28 January 2021

    A Correction to this paper has been published: https://doi.org/10.1038/s41388-021-01645-4

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Acknowledgements

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.

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Conceptualization: AH, AEA; formal analysis: AH and TJP; investigations and interpretations: AH, TJP, NB, VC, CL, ES, and ZTS; resources: ES, TS, DWS, and JWH; writing (original draft): AH; writing (review and editing): AH, TJP, VC, ES, ZTS, DWS. JWH and AEA; funding acquisition: DWS, JWH, and AEA; supervision: AEA.

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Correspondence to Andrew E. Aplin.

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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

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