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

Area of Science:

• Oncology
• Cancer Metabolism
• Ocular Oncology

Background:

• Inactivating mutations in BRCA1-associated protein 1 (BAP1) are linked to metastasis in uveal melanoma (UM), the most lethal adult eye cancer.
• The precise function of BAP1 in UM and the metabolic characteristics of BAP1-mutant UM remain largely undefined.

Purpose of the Study:

• To investigate the metabolic heterogeneity within BAP1-mutant uveal melanoma.
• To identify distinct metabolic subgroups and their dependencies in BAP1-mutant UM.
• To explore the therapeutic implications of identified metabolic differences.

Main Methods:

• Analysis of UM patient tumor samples to identify metabolic subgroups based on oxidative phosphorylation (OXPHOS) gene expression.
• Transcriptomic analysis of BAP1-mutant UM cell lines to confirm metabolic subgroups (OXPHOS^high and OXPHOS^low).
• Integrated RNA sequencing, metabolomics, and molecular analyses to characterize the metabolic pathways utilized by each subgroup.

Main Results:

• BAP1-mutant UM tumors and cell lines exhibit metabolic heterogeneity, classifying into OXPHOS^high and OXPHOS^low subgroups.
• OXPHOS^high BAP1-mutant UM cells rely on glycolysis and nucleotide biosynthesis.
• OXPHOS^low BAP1-mutant UM cells utilize fatty acid oxidation.
• The two metabolic subgroups demonstrate differential responses to various metabolic suppressor agents.

Conclusions:

• Targeting cancer metabolism is a viable therapeutic strategy for BAP1-mutant UM.
• Metabolic heterogeneity in BAP1-mutant UM necessitates tailored therapeutic approaches for optimal efficacy.
• Understanding these distinct metabolic profiles can guide the development of personalized treatments for uveal melanoma.