BAP1 deficient human and mouse uveal melanomas up-regulate a shared EMT pathway

Abstract

Monosomy 3 is a negative indicator for uveal melanoma (UM). A key tumor suppressor on chromosome 3 is the deubiquitinase BAP1, which usually has a second hit in cases with monosomy 3. Here, we investigated the role of Bap1 loss in the GNAQ Q209L mouse UM model. We anticipated that the loss of Bap1 would enhance tumor growth and/or dissemination in a straightforward manner. Instead, our findings revealed a complex relationship between Bap1 status and tumor behavior. Bap1flox/KO was associated with a reduction in the number and size of melanocytic lung lesions. Bap1 heterozygous loss was associated with macroscopic liver lesions. In mice not expressing GNAQ Q209L, Bap1 heterozygous loss caused melanocyte expansion in the choroid, but only in eyes that were structurally abnormal. Finally, transcriptomic analysis identified a shared BAP1-associated gene expression program in mouse and human UM that was strongly enriched for epithelial-to-mesenchymal transition (EMT) and apical junction pathways. Together, these findings suggest that Bap1 influences tumor-cell behavior in a manner that depends on gene dosage, tissue context and the surrounding microenvironment.