STAT3 – the switch of melanoma-associated NRAS mutations

Mutations in NRAS represent almost 20% of driver mutations in malignant melanoma. Clinically, this entity of melanoma is characterized by worse survival rate, relapse rate and therapy response compared to wild type NRAS or BRAF mutations. Moreover, the treatment of NRAS mutated melanoma remains difficult where direct targeting has shown sobering attempts so far. Interestingly, the codon mutational status of NRAS mutations comprises almost exclusively codon 61 mutations (93%) rather than codon 12 or 13 mutations (5%) and depicts different biological behavior in previous studies. Therefore, we focused on revealing the differential activation of cellular signaling pathways of these codon mutations in primary melanocytes and in melanoma-like immortalized melanocytes. We identified STAT3 as the switch of NRASQ61-mediated melanomagenesis to a more transformative phenotype in primary melanocytes and in immortalized melanocytes. In primary melanocytes, NRASQ61-mutated cells were able to circumvent oncogene-induced senescence (OIS), whereas NRASG12/13-mutated cells seemed to be more susceptible to OIS. Furthermore, immortalized melanocytes expressing NRASQ61 presented higher proliferative, colony-forming and migratory capacities than NRASG12/13 cells. Both, in primary and immortalized melanocytes, NRASQ61 expression was associated with STAT3 activation. The analysis of downstream targets of STAT3 revealed MMP2, IL-1ß and IL1R as mediators of NRASQ61-STAT3-axis and its oncogenic phenotype. Additionally, we identified a specific secretory phenotype and kinases activation for each NRASQ61 and NRASG12/13 mutated melanocytes. Taken together, we show novel insights into molecular and cellular mechanisms that are activated upon different NRAS mutations and demonstrate the protumorigenic role of STAT3 in NRAS mutant melanoma which might help improving future therapeutic strategies