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Identification of cells initiating human melanomas

Nature volume 451, pages 345–349 (2008)Cite this article

Abstract

Tumour-initiating cells capable of self-renewal and differentiation, which are responsible for tumour growth, have been identified in human haematological malignancies1,2 and solid cancers3,4,5,6. 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+ subpopulations 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.

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Figure 1: ABCB5 expression analyses.
Figure 2: Tumorigenicity, self-renewal and differentiation of ABCB5 + MMIC.
Figure 3: ABCB5 targeting.

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Acknowledgements

We thank D. Herlyn and M. Herlyn for providing fresh melanoma tissue specimen for our studies. The construction of the tissue microarray was possible only through the collaborative assistance of P. Van Belle, D. Elder, V. Prieto and A. Lazar. The tissue microarrays were performed with the technical assistance of R. Kim, K. Lamb and L. Biagini. We thank A. Baldor for technical assistance with tumour xenotransplantation experiments, and M. Grimm for tissue sectioning and immunohistochemistry. We thank D. Scadden for comments on the manuscript. This work was supported by the NCI/NIH (M.H.F.), a NCI/NIH Specialized Program of Research Excellence (SPORE) in Skin Cancer (T.S.K.) and the Department of Defense (M.H.F.).

Author Contributions T.S., N.Y.F., and M.H.F. planned the project. T.S., N.Y.F., K.Y., A.M.W.-G., Q.Z., S.J. and C.W. carried out experimental work. T.S., G.F.M., N.Y.F., A.M.W.-G., R.C.F. T.S.K., M.H.S. and M.H.F. analysed data. G.F.M., Q.Z., A.M.W.-G, M.G. and L.M.D. provided clinical information and human tissues or performed pathological analysis. T.S., G.F.M., N.Y.F. and M.H.F. wrote the paper. All authors discussed the results and commented on the manuscript.

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Authors and Affiliations

  1. Transplantation Research Center, Children’s Hospital Boston and Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA ,

    Tobias Schatton, Natasha Y. Frank, Kazuhiro Yamaura, Stefan Jordan, Mohamed H. Sayegh & Markus H. Frank

  2. Department of Pathology and,,

    George F. Murphy & Qian Zhan

  3. Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Natasha Y. Frank

  4. Department of Surgery, University of Würzburg Medical School, 97080 Würzburg, Germany

    Ana Maria Waaga-Gasser & Martin Gasser

  5. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA,

    Lyn M. Duncan

  6. Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA,

    Carsten Weishaupt, Robert C. Fuhlbrigge & Thomas S. Kupper

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  1. Tobias Schatton
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Correspondence to Markus H. Frank.

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Competing interests

All financial and material support for this research and work are identified in the manuscript; they include solely the U.S. National Institutes of Health and the U.S. Department of Defense. The authors declare the following potential conflicts of interest: M.H.F. and M.H.S. are co-inventors of the ABCB5-related U.S. patent 6,846,883 (Gene encoding a multidrug resistance human P-glycoprotein homologue on chromosome 7p15-21 and uses thereof) assigned to Brigham and Women’s Hospital, Boston, Massachusetts.

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Schatton, T., Murphy, G., Frank, N. et al. Identification of cells initiating human melanomas. Nature 451, 345–349 (2008). https://doi.org/10.1038/nature06489

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