Journal article
BAP1 Loss Affords Lipotoxicity Resistance in Uveal Melanoma
Pigment cell and melanoma research, v 38(3), e70021
May 2025
PMID: 40300851
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Uveal melanoma (UM) is an aggressive intraocular malignancy. Despite effective control of primary tumors, ~50% of UM patients develop metastases, with the liver being the predominant secondary site. BAP1 deficiency, present in ~80% of metastatic UM cases, is strongly associated with increased metastatic risk and poor prognosis. In silico analysis of UM patient samples suggests that reduced BAP1 is linked to enhanced expression of genes involved in fatty acid processing; therefore, we hypothesize that BAP1 deficiency primes UM cells for survival in the hepatic microenvironment by enhancing lipid tolerance and oxidative stress responses. Our findings demonstrate BAP1-mutant UM resist lipotoxicity, whereas BAP1-competent UM exhibit sensitivity due to lipid peroxide accumulation-a hallmark of ferroptotic-like stress, and a response that can be mitigated by ferroptosis inhibition. Using an ex vivo liver slice model, we found that disrupting lipid metabolism with atorvastatin, an HMG-CoA reductase inhibitor, reduced tumor burden of BAP1-mutant UM. Moreover, we demonstrate a positive correlation between BAP1 and an epigenetic regulator of lipid homeostasis, ASXL2. Notably, ASXL2 depletion in BAP1-competent UM phenocopies the lipotoxicity resistance observed in BAP1-mutant UM-an effect that may be mediated by altered PPAR expression. This study reveals a novel mechanism linking BAP1 expression to lipid sensitivity via ASXL2, providing insights into liver tropism and potential therapeutic avenues for metastatic uveal melanoma.
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Details
- Title
- BAP1 Loss Affords Lipotoxicity Resistance in Uveal Melanoma
- Creators
- C J Cunanan - Drexel UniversityA Amirfallah - Drexel UniversityA B Sanders - Drexel UniversityK C Gallant - Drexel UniversityM R Cavallo - Drexel UniversityE A Homer - Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAO S El Naggar - Drexel UniversityJ K Farnan - Drexel UniversityG Romano - Drexel UniversityJ L Hope - Sidney Kimmel Comprehensive Cancer CenterJ G Jackson - Drexel UniversityE J Hartsough (Corresponding Author) - Drexel University
- Publication Details
- Pigment cell and melanoma research, v 38(3), e70021
- Publisher
- Wiley
- Number of pages
- 15
- Grants
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Pharmacology and Physiology
- Web of Science ID
- WOS:001497772100012
- Scopus ID
- 2-s2.0-105004185086
- Other Identifier
- 991022050746704721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Cell Biology
- Dermatology
- Oncology