Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Department of Pathology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Oncogene. 2021 Jan;40(3):618-632. doi: 10.1038/s41388-020-01554-y. Epub 2020 Nov 18.
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 OXPHOS or OXPHOS subgroups. Integrated RNA sequencing, metabolomics, and molecular analyses showed that OXPHOS BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOS 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.
癌细胞代谢是一个可靶向的弱点；然而，需要精确理解代谢异质性。BRCA1 相关蛋白 1（BAP1）失活突变与葡萄膜黑色素瘤（UM）的转移有关，UM 是最致命的成人眼癌。BAP1 在 UM 中的功能仍不清楚。基于氧化磷酸化（OXPHOS）基因表达，对 BAP1 突变型 UM 肿瘤的患者样本分析将 BAP1 突变型 UM 肿瘤分为两个亚组，表明代谢异质性。与患者数据一致，BAP1 突变型 UM 细胞系的转录组分析也显示出 OXPHOS 或 OXPHOS 亚组。整合 RNA 测序、代谢组学和分子分析表明，OXPHOS BAP1 突变型 UM 细胞利用糖酵解和核苷酸生物合成途径，而 OXPHOS BAP1 突变型 UM 细胞则利用脂肪酸氧化。此外，这两个亚组对不同类别的代谢抑制剂有反应。我们的研究结果表明，针对 BAP1 突变型 UM 的癌症代谢是一种很有前途的治疗选择；然而，由于代谢异质性，可能需要采用量身定制的方法。
