The incidence of melanoma (MM), the most lethal of all types of skin cancer, has increased steadily for the last 50 years among populations of European descent. Over 100,000 new cases are diagnosed and more than 22,000 people die each year from MM in Europe. About 5,000 cases and 1,000 deaths correspond to Spain. Treatment options for advanced MM remain limited and rarely curative.

Knowledge of the molecular alterations in key signaling pathways associated with MM onset and progression led to approval by the FDA of two new targetted drugs, Vemurafenib and Dabrafenib, but many MMs do not respond at all to these drugs and, even more disappointingly, acquired resistance has been shown to follow invariably impressive initial responses. Thus, the identification of new therapeutic targets remains a primary goal.

MM is an heterogeneous disease even in patients with similar clinical features. Long-term survival for patients with advanced MM is low, with a 5-year survival for metastatic MM of 11%, but a large number of patients have a variable outcome. This variability warns of difficulties to select patients who could benefit from treatments.

Thus, to improve diagnosis and management of the disease, it is crucial to identify the molecular causes of heterogeneity, so as to define and validate new prognostic markers.

Risk factors for MM

Epidemiological studies identified personal characteristics like fair skin, light hair and eyes and high number of melanocytic naevi in addition to environmental agents such as ultraviolet radiation (UVR). These phenotypic traits are dependent on the melanocortin-1-receptor gene which is considered a moderate-risk gene for MM susceptibility and a key regulator of skin pigmentation.

MC1R signaling

Upon activation by alpha-melanocyte stimulating hormone, MC1R expressed in melanocytes signals through the cAMP and the mitogen-activated protein kinases ERK1 and ERK2 pathways to activate eumelanin pigment production, antioxidant defenses and DNA repair pathways. This combination of pigmentary and nonpigmentary actions protects the skin from carcinogenic UVR, but paradoxically it may also contribute to a more malignant phenotype in transformed melanocytes.

Polyamine metabolism

The ubiquitous polyamines spermidine, spermine and putrescine are small basic molecules which modulate key biological processes such as nucleic acids and protein synthesis and cell signaling. Dysregulation of polyamine metabolism has been demonstrated in most cancer types, including MM.

MC1R-triggered signaling cues

Several observations, including upregulation of polyamine biosynthesis by alpha-MSH in mouse MM cells, point to a crosstalk of polyamine-dependent and MC1R-triggered signaling cues in melanocytes and MM cells.

MGRN1 gene

MC1R signaling is also tightly regulated by Mahogunin Ring Finger 1 (MGRN1). The MGRN1 gene was identified by positional cloning of Mahoganoid, a mouse coat color mutation associated with fur darkening, with pleiotropic effects including congenital heart defects and spongiform neurodegeneration in adult mice. Preliminary evidence suggests that MGRN1 contributes to regulation of core cellular processes such as organelle trafficking, mitochondrial metabolism, cytoskeletal organization and cell cycle progression.

These processes are likely deregulated in MM and reduced expression of MGRN1 is associated with a higher survival of MM patients according to analysis of public databases. However, the role of MGRN1 as a determinant of the malignant phenotype of MM cells remains to be proven.

Proposed study

We propose an integrated study of MC1R signaling, MGRN1 function and polyamine biology in melanocytes and MM cells, in order to gain a deeper knowledge of their physiological role as determinants of melanocyte proliferation and differentiation and of their implication in MM. The proposal will contribute to shift our research towards preclinical studies. It could lead to the identification of new and improved prognostic markers for high risk MM and of a new potential therapeutic target.