We demonstrate that EMT-TFs’ expression switching, leading to Zeb1 overexpression, directly regulates the expression of the tetraspanin 8 (Tspan8) transmembrane protein and that Tspan8 expression is sufficient to remodel the melanoma cell morphology, decrease the intrinsic cell stiffness, and induce dermal invasion. The gene discussed is TSPAN8; the disease is melanoma.