BAP1 promotes switch from pluripotency to differentiation during development in multiple lineages

JEFFIM KUZNETSOV; TRISTÁN AGÜERO; STEFANIE KURTENBACH; MATTHEW G. FIELD; MARY LOU KING; WILLIAM HARBOUR

Washington

Congreso; American Association of Cancer Research; 2017

Uveal melanoma is the most common primary intraocular tumor,arising in the iris, choroid or ciliary body. Our lab discovered that mutationsin the tumor suppressor BAP1 are strongly associated with metastasis and deathin patients with uveal melanoma. Subsequently, other cancers have been found toharbor BAP1 mutations, including skin melanoma, kidney cancer, mesothelioma andothers. Germline BAP1 mutations are responsible for a newly described geneticcancer syndrome. Therapeutic molecules that reverse the effects of BAP1mutations could represent a potent new treatment strategy for BAP1-mutantcancers. Unfortunately, there are several obstacles to developing suchtherapies. First, BAP1 is a tumor suppressor that is inactivated by mutations,such that targeted therapy would need to be directed against downstreameffectors that are deregulated by BAP1 loss. Second, the effectors of BAP1 thatare relevant to cancer are not known. Third, BAP1 is difficult to study incultured cells because BAP1 loss results in cell cycle exit and stem cell-likebehavior. While our initial studies in vitro suggest a role for BAP1 indevelopmental processes, a comprehensive in vivo strategy is needed todetermine the role and mechanisms of action of BAP1 in the neural crestlineage. These ideas led us to shift from using in vitro to in vivomodels for studying BAP1. Consequently, we have selected the frog speciesXenopus laevis (African clawed frog) for studying the normal function of BAP1and the effects of BAP1 loss in vivo. The BAP1 gene is highly conserved,especially in comparison to zebrafish, the other commonly used developmentalmodel. Remarkably, xBAP1 protein shares 91% similarity to the human homologue.