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

Abstract

SUMMARYMonosomy 3 is a negative indicator for uveal melanoma (UM). A key tumor suppressor on chromosome 3 is the deubiquitinaseBAP1, which usually has a second hit in cases with monosomy 3. Here, we investigated the role ofBap1loss in the GNAQQ209Lmouse UM model. We found that heterozygousBap1mutations increased the proportion of lung lesions reaching an unusually large size and permitted the growth of liver lesions. Comparison of RNAseq data from mouse and human UM identified a set of 270 genes differentially expressed in the same direction whenBAP1is mutant. The most significant pathway in this gene set was Epithelial to Mesenchymal Transition (EMT). The expression of five apical junction complex genes known to be down-regulated in association with EMT was very significantly correlated with survival in human UM patients. Activation of EMT throughBap1deficiency could increase melanoma plasticity and adaptation to new microenvironments.