Our study shows that hypoxic melanoma cells, either Hs294T or A375, isolated from P0 spheres express an high capacity to induce P1 spheres, level of CD133 and higher ability of 3D invasiveness and 2D motility also in the presence of Etoposide, a pro-apoptotic agent active on topoisomerase II [48]. Here, PROM1 is linked to melanoma.