Ricerc@Sapienza

Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. Despite the great progress of therapeutic strategies, long-term survival of 5 years and more was only achieved in 5-10% of patients with metastatic melanoma regardless of the specific therapeutic strategy used.
Based on the Reflectance confocal microscopy (RCM), which gives the opportunity to analyze architectural and cytological features in horizontal sections in vivo, is possible to identify four distinct melanoma subtypes: 1) Dendritic-cell melanomas; 2) Round cell melanomas; 3) Dermal-nest melanomas; 4) Combined-type melanomas.
Two-Pore Channel 2 (TPC2), an ionic channel present on the membrane of melanosomes and other acidic intracellular Ca2+ stores, is basic for the metastatic behaviour of other cancer cells and recently we demonstrated that Naringenin (Nar), a flavanone present in citrus fruit and other vegetables, is a newly discovered inhibitor of TPC2; in melanoma cell lines the TPC2 activating second messenger NAADP controls growth and invasion, in vitro and in vivo.
Our hypothesis is that melanoma subtypes are endowed with different genetic signatures and signaling pathways, that in turn account for diverse biologic behaviors and response to therapy. In addition, we demonstrated that melanosomal TPC2/NAADP signaling is crucial for melanoma progression, and that targeting TPC2 can prevent growth and metastatic behaviour of melanoma cells. In particular it is expected that preventing the release of melanosomes/extracellular vesicles from early stage melanoma, the formation of the tumor niche would be impaired and metastatic invasion consequently blocked.
Our aim is to assess the involvement of the melanosome and of autophagy in the control of melanoma growth and invasion and to test the impact of pharmacologic/genetic inhibition of TPC2 in RCM melanoma subtypes with different aggressiveness and susceptibility to therapy.