Dissertation
BAP1 loss confers lipotoxicity resistance in uveal melanoma
Doctor of Philosophy (Ph.D.), Drexel University
Nov 2024
DOI:
https://doi.org/10.17918/00010791
Abstract
Uveal melanoma (UM) is a rare and aggressive intraocular malignancy arising from melanocytes in the uveal tract. Despite effective local control of primary tumors, approximately 50% of UM patients develop metastases, with the liver being the predominant site of metastatic spread. BAP1 deficiency, present in about 80% of metastatic UM cases, is strongly associated with increased metastatic risk and poor prognosis. Analysis of UM patient samples reveals negative correlations between BAP1 expression and genes involved in long-chain fatty acid metabolism and lipase activity. We hypothesized that BAP1 deficiency primes UM cells for survival in the hepatic microenvironment by enhancing lipid processing and oxidative stress management. Our findings show that BAP1-deficient UM cells tolerate long-chain fatty acid-induced lipotoxicity. Alternatively, BAP1-competent UM is sensitive to lipotoxicity, an effect associated with lipid peroxide accumulation. Notably, this response can be rescued with pharmacological inhibition of ferroptosis. When exposed to liver-secreted factors, only BAP1-competent UM cells respond by upregulating lipid metabolism and oxidative stress management markers, suggesting BAP1-deficient UM possesses inherent stress resistance. In an ex vivo liver MUM model, BAP1-deficient UM cells are highly sensitized to fatty acid metabolism inhibition by atorvastatin, resulting in increased lipid peroxides and reduced tumor burden. Mechanistically, we uncovered a novel relationship between BAP1 and ASXL2, a known regulator of lipid homeostasis. BAP1 loss reduces ASXL2 expression, disrupting their deubiquitinating complex and increasing histone H2A ubiquitination. ASXL2 depletion in BAP1-competent cells recapitulates the lipotoxicity resistance of BAP1-deficient cells, an effect that may be linked to altered PPAR expression patterns. This study reveals a novel mechanism linking BAP1 deficiency to metabolic rewiring in UM through ASXL2 dysregulation, providing insights into liver tropism and opening new possibilities for targeted therapies in metastatic uveal melanoma.
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Details
- Title
- BAP1 loss confers lipotoxicity resistance in uveal melanoma
- Creators
- Camille Jessica Cunanan
- Contributors
- Edward J. Hartsough (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 145 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022019119604721