In summary, we report the novel finding that within a human-differentiated epidermis, Tspan8 expression in melanoma cells cooperate with surrounding keratinocytes to promote dermal invasion by instigating keratinocyte-produced MMP-3 activation and decreasing melanoma-derived TIMP-1 levels, leading to keratinocyte-originated MMP-9 activation process, and subsequent DEJ-collagen IV degradation. Here, TIMP1 is linked to melanoma.