PROS1 expression is regulated by BAP1 in uveal melanocytes and melanomas.

Uveal melanoma is a highly metastatic cancer of the eye which is notoriously resistant to therapy. Elucidating the mechanisms of metastasis in order to devise effective therapies has been a major challenge.

The strongest genetic risk factor for metastasis in uveal melanoma is the mutational inactivation of the BAP1 tumor-suppressor gene. However, it remains unknown how BAP1 loss promotes tumor progression. Here, we show that BAP1 loss leads to increased expression of PROS1 in uveal melanocytes and melanoma cells, which in turn leads to phosphorylation and activation of the receptor tyrosine kinase MERTK on adjacent macrophages, driving them into a suppressive M2-polarized state.