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Dissertation
BAP1 loss in uveal melanoma drives selenoproteome dependency and leverages liver selenoprotein P to support metastatic growth
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2026
DOI:
https://doi.org/10.17918/00011516
Abstract
Uveal melanoma (UM) is the most common intraocular malignancy in adults, arising in melanocytes within the uveal tract. Although local disease can be effectively controlled by radiation or enucleation, nearly half of patients ultimately develop fatal liver metastases. Hepatic metastases are strongly associated with loss of the tumor suppressor BAP1, yet the metabolic adaptations that enable BAP1-deficient UM cells to survive and proliferate within the liver remain poorly understood. Transcriptomic analyses revealed that mutant BAP1 UM tumors exhibit elevated expression of genes involved in glutathione (GSH) synthesis. Analysis of human UM cell lines revealed that mutant BAP1 UM cell lines have increased total thiols and an elevated GSH:GSSG ratio, alongside heightened sensitivity to GSH depletion. Given that GSH serves as a cofactor for antioxidant selenoproteins such as GPX4, we investigated the role of selenoproteins in UM liver metastases. We found that mutant BAP1 UM cells exhibited increased dependence on GPX4, as inhibition of GPX4 induced lipid peroxidation and cell death. Because GPX4 requires selenocysteine for its synthesis and activity, we next investigated whether mutant BAP1 UM cells exhibit altered selenium acquisition pathways. Mutant BAP1 UM cells displayed enhanced selenoproteome synthesis and increased utilization of liver-derived selenoprotein P (SEPP) through the receptor LRP8. Moreover, disruption of this BAP1-associated selenoprotein network via LRP8 interference impaired the growth of hepatic lesions and reduced tumor viability in human liver slice models, thereby identifying a potential therapeutic target for metastatic UM. Together, these findings identify a mutant BAP1-associated selenoprotein-dependent vulnerability in metastatic UM.
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Details
- Title
- BAP1 loss in uveal melanoma drives selenoproteome dependency and leverages liver selenoprotein P to support metastatic growth
- Creators
- Alyssa Bree Monteleone-Haught
- Contributors
- Edward J. Hartsough (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- xxi, 173 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022200852304721