Identification of cells initiating human melanomas

Tumour- initiating cells capable of self- renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies(1,2) and solid cancers(3-6). If such minority populations are associated with tumour progression in human patients, specific targeting of tumour- initiating cells could be a strategy to eradicate cancers currently resistant to systemic therapy. Here we identify a subpopulation enriched for human malignant- melanoma- initiating cells ( MMIC) defined by expression of the chemoresistance mediator ABCB5 ( refs 7, 8) and show that specific targeting of this tumorigenic minority population inhibits tumour growth. ABCB5(+) tumour cells detected in human melanoma patients show a primitive molecular phenotype and correlate with clinical melanoma progression. In serial human- to-mouse xenotransplantation experiments, ABCB5(+) melanoma cells possess greater tumorigenic capacity than ABCB5(-) bulk populations and re- establish clinical tumour heterogeneity. In vivo genetic lineage tracking demonstrates a specific capacity of ABCB5(+) sub-populations for self- renewal and differentiation, because ABCB5(+) cancer cells generate both ABCB5(+) and ABCB5(-) progeny, whereas ABCB5(-) tumour populations give rise, at lower rates, exclusively to ABCB5(-) cells. In an initial proof- of- principle analysis, designed to test the hypothesis that MMIC are also required for growth of established tumours, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody- dependent cell- mediated cytotoxicity in ABCB5(+) MMIC, exerted tumour- inhibitory effects. Identification of tumour- initiating cells with enhanced abundance in more advanced disease but susceptibility to specific targeting through a defining chemoresistance determinant has important implications for cancer therapy.