The conventional diagnostic and prognostic biomarkers (i.e. Clark Level (CL), Breslow Index (BI) or immunohistochemical markers 2) seem insufficient to distinguish precisely primary epidermis-limited neoplasms from aggressive or advanced/metastatic melanomas, and to assess the outcome for individual patients. ...additional relevant biomarkers are needed to predict the individual risk of metastasis and monitor disease progression. ...we identified several Tspan8 transcriptional regulators whose deregulation leads to Tspan8 expression 3, 5, 6, which could help to design new therapeutic strategies targeting Tspan8. Tspan8 protein expression in human primary melanomas was correlated with a higher propensity to give rise to distant metastases and an increased risk of death To evaluate the impact of Tspan8 expression at the protein level, we performed Tspan8 immunohistochemical staining analysis in a cohort of 100 primary melanoma samples: 73% of primary melanomas were positive for Tspan8 protein expression (sup. Tspan8 protein seemed more frequently expressed in the thinnest melanomas from patients dead during the 5-year period after diagnosis (92.3% of samples). ...the thinnest primary melanomas seemed to express the highest levels of Tspan8 protein (immunointensity score 4 exclusively in < 1 mm samples), especially in patients’ dead 5-years after diagnosis (60% of immunointensity scores 3–4; Fig. 2c).