Malignant Melanoma is a highly aggressive form of skin cancer known to metastasize to different organs among which lung is the most frequently associated to fatal outcome. TPC2 is a calcium/sodium channel, localized predominantly on the acidic stores membranes such as late-endosomes, lysosomes and melanosomes. There is increasing evidence that links two-pore channel 2 (TPC2) to cancer, revealing the potential applications of TPC2 as a biomarker in the definition of tumour types, susceptibility, prognosis, response and cancer outcomes. Our central hypothesis is that two-pore channels play a pivotal role in the processes of tumorigenesis and metastasis and that they are possible cancer biomarkers and targets for cancer treatment and specifically for melanoma. We expect to identify a set of clinical and dermoscopic different melanoma subtypes features that significantly correlate with a novel "signature" encompassing genetic mutation and biologic alteration in NAADP/TPC2 signaling pathways. We will examine TPC2 profiling as novel and promising detection, diagnostic, prognostic and predictive melanoma biomarkers. In addition, we will investigate the role of TPC2 in angiogenesis, tumorigenesis and metastasis processes using functional assays and by overexpression or silencing of the TPCN2 gene in in vitro models. Moreover, we will develop in vitro models to examine the role of the identified novel mutations and level of expression of the TPCN2 gene during melanoma progression formation and cancer cell migration in different melanoma subtypes. These findings will add to our understanding of the mechanisms of tumourigenesis and metastasis and could help identify new ways to diagnose and treat melanoma and other metastatic cancers.
