Nonclassical Sex Hormone Signaling in Melanocytes and Melanoma

The primary pigment in mammalian skin and hair is melanin, which is synthesized locally by differentiated melanocytes and transferred into surrounding epidermal keratinocytes and hair shafts. Because pigmentation differences are often readily visible clinically, melanocyte function is known to correlate with changes in environment, as well as physiologic and pathologic changes in other organ systems. We utilized these clinical associations to inspire the hypothesis that sex hormones influence melanocyte biology. For over 2,000 years, it has been appreciated that pregnancy is associated with changes in skin pigmentation, but the specific processes, hormones, receptors, and downstream signaling cascades responsible have remained unknown. During this thesis work, we discovered that estrogen and progesterone reciprocally regulate melanocyte pigmentation and differentiation state. We also determined that melanocytes do not express classical nuclear estrogen or progesterone receptors, and rather, sex hormones signal through two nonclassical G protein-coupled receptors: the G protein-coupled estrogen receptor (GPER) and progestin and adipoQ receptor 7 (PAQR7). Specific activation of these receptors with selective small molecule agonists that do not activate the nuclear hormone receptors, recapitulates the entirety of the estrogen and progesterone effects in melanocytes. GPER and PAQR7 agonists may serve as new therapeutic agents for disorders of pigmentation. We then utilized the discovery that GPER signaling drives differentiation in normal melanocytes to develop a novel differentiation-based therapy for melanoma. Many lines of clinical evidence suggest that female sex and history of prior pregnancies are associated with favorable melanoma outcomes, although the mechanism for this presumed protective effect were previously unknown. We determined that GPER signaling in melanoma cells drives a durable differentiation program that slows tumor growth, and renders tumor cells more susceptible to clearance by the immune system. Systemic treatment of melanoma-bearing mice with specific GPER agonists was well tolerated, and had dramatic combinatorial effects when combined with immune checkpoint blockade, resulting in complete tumor clearance and long-term anti-tumor immunity. Thus, this work identified previously unknown mechanisms by which female sex steroids influence melanocytes, and utilized that understanding to develop a novel melanoma therapy that establishes, for the first time, the therapeutic benefit of combining differentiation drivers with cancer immunotherapy.