In summary, using a combination of in vitro, in vivo and in situ approaches, we uncovered a hitherto unappreciated function of Tspan8 in negatively regulating β1 integrin-dependent adhesion and avidity through ILK, which sets off the aggressiveness of melanoma cells by decreasing adhesive interaction with the surrounding matrix environment and promoting tumor escape. The gene discussed is ILK; the disease is melanoma.