Gq/11-mediated GPCR signaling in melanoma pathogenesis and therapy

Aberrant expression, overexpression or signal reprogramming of G-protein coupled receptors (GPCR) and G-proteins have been linked to cancer development and progression. The important role of GPCR-Gαq signaling in melanocyte neoplasia became apparent with the discovery of somatic Gnaq mutations in blue melanocytic nevi in the skin and in uveal melanomas. The principle goal of our proposal is to gain deeper insight into the role of Gnaq/11 signaling in melanoma biology. Our work is based on the general hypothesis that activated Gnaq/11 signaling can promote melanoma cell proliferation and tumor growth but also migration and metastatic disease progression in a defined microenvironmental context that provides strong receptor tyrosine kinase driven survival signaling. From our analyses we expect new general insights into the molecular mechanisms why and how mutant Gαq/11 signaling drives growth and metastasis of certain melanoma subtypes. We also hope to provide a basis for the development of novel therapeutic approaches targeting deregulated Gαq/11 signaling which is particularly important for patients with uveal melanoma.