A study reveals that single human melanoma cells can form tumors more efficiently in highly immunocompromised NOD/SCID Il2rg^-/- mice than in standard NOD/SCID mice. Using modified xenotransplantation assays, researchers found that approximately 25% of unselected melanoma cells from 12 patients formed tumors, with an average of 27% of cells from four patients forming tumors in single-cell transplants. These findings suggest that tumorigenic melanoma cells are more common than previously thought, challenging the cancer stem-cell model which posits that only rare cells have tumorigenic potential. The study also shows that melanoma-initiating cells are phenotypically heterogeneous and that markers used to identify them in NOD/SCID mice may not distinguish tumorigenic from non-tumorigenic cells in more permissive assays. The results indicate that xenotransplantation assays can be optimized to detect higher frequencies of tumorigenic cells, suggesting that some human cancers may have common tumorigenic cells. The study highlights the importance of optimizing xenotransplantation assays to better understand cancer biology and develop more effective therapies.A study reveals that single human melanoma cells can form tumors more efficiently in highly immunocompromised NOD/SCID Il2rg^-/- mice than in standard NOD/SCID mice. Using modified xenotransplantation assays, researchers found that approximately 25% of unselected melanoma cells from 12 patients formed tumors, with an average of 27% of cells from four patients forming tumors in single-cell transplants. These findings suggest that tumorigenic melanoma cells are more common than previously thought, challenging the cancer stem-cell model which posits that only rare cells have tumorigenic potential. The study also shows that melanoma-initiating cells are phenotypically heterogeneous and that markers used to identify them in NOD/SCID mice may not distinguish tumorigenic from non-tumorigenic cells in more permissive assays. The results indicate that xenotransplantation assays can be optimized to detect higher frequencies of tumorigenic cells, suggesting that some human cancers may have common tumorigenic cells. The study highlights the importance of optimizing xenotransplantation assays to better understand cancer biology and develop more effective therapies.