ARF6 is a targetable node that orchestrates signaling of multiple oncogenic pathways in cutaneous and uveal melanoma

Melanoma is a malignant tumor that develops from melanocytes, which are pigmented cells primarily found in the epidermis, eye, and mucosal epithelia. Melanomas can occur in any tissue containing melanocytes. Although both cutaneous and uveal melanomas are derived from melanocytes, they have significant differences in terms of genetic alterations, metastatic pattern, tumorigenesis, and therapeutic response. In this dissertation, I present the results of studies that explore the role of the small GTPase ARF6 in cutaneous and uveal melanoma. These studies show that ARF6 is required both for invasion and metastasis in cutaneous melanoma and for orchestrating oncogenic G protein-mediated signaling pathways that promote uveal melanoma cell proliferation. In cutaneous melanoma cells, WNT5A-FZD4-LRP6 signaling activates ARF6 via the guanine nucleotide exchange factor (GEF) GEP100. ARF6 activation promotes the release of -catenin from cell-surface N-cadherin, thereby increasing the pool of cytoplasmic and nuclear -catenin with a subsequent induction of transcription, invasion, and metastasis. As WNT signaling is implicated in many cancers, these findings suggest that a WNT-ARFGEF-ARF signaling module may play an important role in the metastasis of multiple cancers. Uveal melanoma is the most common primary intraocular tumor. Activating mutations in GNAQ and GNA11, which encode members of the q class of the G-protein alpha subunit (Gq), are the primary drivers of uveal melanoma tumorigenesis. I show iv that oncogenic GNAQ forms a complex with GEP100 to activate ARF6, which in turn induces all known GNAQ-mediated signaling pathways as well as the relocalization of -catenin from the cell surface to the nucleus. These findings indicate that ARF6 is the primary immediate effector of an oncogenic GNAQ/GEP100 complex that regulates multiple signaling pathways shown to be important in the control of uveal melanoma tumorigenesis and growth. These results not only provide an improved understanding of the molecular mechanism underlying Gq-mediated tumorigenesis but also suggest a new target for therapeutic intervention in uveal melanoma.