Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma

Nature Cell Biology volume 14, pages 882–890 (2012)Cite this article

Subjects

Abstract

Giant congenital naevi are pigmented childhood lesions that frequently lead to melanoma, the most aggressive skin cancer. The mechanisms underlying this malignancy are largely unknown, and there are no effective therapies. Here we describe a mouse model for giant congenital naevi and show that naevi and melanoma prominently express Sox10, a transcription factor crucial for the formation of melanocytes from the neural crest. Strikingly, Sox10 haploinsufficiency counteracts NrasQ61K-driven congenital naevus and melanoma formation without affecting the physiological functions of neural crest derivatives in the skin. Moreover, Sox10 is also crucial for the maintenance of neoplastic cells in vivo. In human patients, virtually all congenital naevi and melanomas are SOX10 positive. Furthermore, SOX10 silencing in human melanoma cells suppresses neural crest stem cell properties, counteracts proliferation and cell survival, and completely abolishes in vivo tumour formation. Thus, SOX10 represents a promising target for the treatment of congenital naevi and melanoma in human patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Histological analysis of the skin of Tyr::NrasQ61K mice reveals lesions similar to human giant congenital naevi.
Figure 2: SOX10 expression is a reliable marker for giant congenital naevi, primary melanoma and melanoma metastases in Tyr::NrasQ61KINK4a−/− mice and in human patients.
Figure 3: Sox10 haploinsufficiency counteracts Tyr::NrasQ61K-mediated hyperpigmentation and melanoma formation by counteracting NrasQ61K-dependent proliferation.
Figure 4: Sox10 function is crucial for the maintenance of already established melanocytic lesions in Tyr::NrasQ61K mice and is required for proliferation and survival of cells with tumorigenic potential in human melanoma cell lines.
Figure 5: SOX10 is required for proliferation and survival of cells with tumorigenic potential in human melanoma cell lines and SOX10 knockdown induces fate switch in melanoma cells.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Bauer, J., Curtin, J. A., Pinkel, D. & Bastian, B. C. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J. Invest. Dermatol. 127, 179–182 (2007).

    Article  CAS  Google Scholar 

  2. Ghosh, P. & Chin, L. Genetics and genomics of melanoma. Expert. Rev. Dermatol. 4, 131–143 (2009).

    Article  CAS  Google Scholar 

  3. Ichii-Nakato, N. et al. High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi. J. Invest. Dermatol. 126, 2111–2118 (2006).

    Article  CAS  Google Scholar 

  4. Ackermann, J. et al. Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background. Cancer Res. 65, 4005–4011 (2005).

    Article  CAS  Google Scholar 

  5. Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996).

    Article  CAS  Google Scholar 

  6. Britsch, S. et al. The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 15, 66–78 (2001).

    Article  CAS  Google Scholar 

  7. Sommer, L. Generation of melanocytes from neural crest cells. Pigment Cell Melanoma Res. 24, 411–421 (2011).

    Article  CAS  Google Scholar 

  8. Wong, C. E. et al. Neural crest-derived cells with stem cell features can be traced back to multiple lineages in the adult skin. J. Cell Biol. 175, 1005–1015 (2006).

    Article  CAS  Google Scholar 

  9. Kuhlbrodt, K. et al. Functional analysis of Sox10 mutations found in human Waardenburg-Hirschsprung patients. J. Biol. Chem. 273, 23033–23038 (1998).

    Article  CAS  Google Scholar 

  10. Civenni, G. et al. Human CD271-positive melanoma stem cells associated with metastasis establish tumor heterogeneity and long-term growth. Cancer Res. 71, 3098–3109 (2011).

    Article  CAS  Google Scholar 

  11. Nonaka, D., Chiriboga, L. & Rubin, B. P. Sox10: a pan-schwannian and melanocytic marker. Am. J. Surg. Pathol. 32, 1291–1298 (2008).

    Article  Google Scholar 

  12. Bakos, R. M. et al. Nestin and SOX9 and SOX10 transcription factors are coexpressed in melanoma. Exp. Dermatol. 19, e89–e94 (2010).

    Article  Google Scholar 

  13. Agnarsdottir, M. et al. SOX10 expression in superficial spreading and nodular malignant melanomas. Melanoma Res. 20, 468–478 (2010).

    Article  CAS  Google Scholar 

  14. Flammiger, A. et al. SOX9 and SOX10 but not BRN2 are required fornestin expression in human melanoma cells. J. Invest. Dermatol. 129, 945–953 (2009).

    Article  CAS  Google Scholar 

  15. Mihic-Probst, D. et al. Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int. J. Cancer 121, 1764–1770 (2007).

    Article  CAS  Google Scholar 

  16. Arnheiter, H. The discovery of the microphthalmia locus and its gene. Mitf. Pigment Cell Melanoma Res. 23, 729–735 (2010).

    Article  CAS  Google Scholar 

  17. Paratore, C., Goerich, D. E., Suter, M. & Sommer, L. Survival and glial fate acquisition of neural crest cells are regulated by an interplay between the transcription factor Sox10 and extrinsic combinatorial signaling. Development 128, 3949–3961 (2001).

    CAS  PubMed  Google Scholar 

  18. Herbarth, B. et al. Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. Proc. Natl Acad. Sci. USA 95, 5161–5165 (1998).

    Article  CAS  Google Scholar 

  19. Paratore, C., Eichenberger, C., Suter, U. & Sommer, L. Sox10 haploinsufficiency affects maintenance of progenitor cells in a mouse model of Hirschsprung disease. Hum. Mol. Genet. 11, 3075–3085 (2002).

    Article  CAS  Google Scholar 

  20. Bondurand, N. et al. A molecular analysis of the yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies. Hum. Mol. Genet. 8, 1785–1789 (1999).

    Article  CAS  Google Scholar 

  21. Pingault, V. et al. SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat. Genet. 18, 171–173 (1998).

    Article  CAS  Google Scholar 

  22. Southard-Smith, E. M. et al. The Sox10(Dom) mouse: Modeling the genetic variation of Waardenburg- Shah (WS4) syndrome. Genome Res. 9, 215–225 (1999).

    CAS  PubMed  Google Scholar 

  23. Lang, D. et al. Pax3 functions at a nodal point in melanocyte stem cell differentiation. Nature 433, 884–887 (2005).

    Article  CAS  Google Scholar 

  24. Nishimura, E. K. et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature 416, 854–860 (2002).

    Article  CAS  Google Scholar 

  25. Rabbani, P. et al. Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell 145, 941–955 (2011).

    Article  CAS  Google Scholar 

  26. Kim, J., Lo, L., Dormand, E. & Anderson, D. J. SOX10 maintains multipotency and inhibits neuronal differentiation of neural crest stem cells. Neuron 38, 17–31 (2003).

    Article  CAS  Google Scholar 

  27. Bondurand, N., Natarajan, D., Barlow, A., Thapar, N. & Pachnis, V. Maintenance of mammalian enteric nervous system progenitors by SOX10 and endothelin 3 signalling. Development 133, 2075–2086 (2006).

    Article  CAS  Google Scholar 

  28. John, N., Cinelli, P., Wegner, M. & Sommer, L. Transforming growth factor beta-mediated Sox10 suppression controls mesenchymal progenitor generation in neural crest stem cells. Stem Cells 29, 689–699 (2011).

    Article  CAS  Google Scholar 

  29. Finzsch, M. et al. Sox10 is required for Schwann cell identity and progression beyond the immature Schwann cell stage. J. Cell Biol. 189, 701–712 (2010).

    Article  CAS  Google Scholar 

  30. Stolt, C. C., Lommes, P., Hillgartner, S. & Wegner, M. The transcription factor Sox5 modulates Sox10 function during melanocyte development. Nucleic Acids Res. 36, 5427–5440 (2008).

    Article  CAS  Google Scholar 

  31. Boiko, A. D. et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 466, 133–137 (2010).

    Article  CAS  Google Scholar 

  32. Bosenberg, M. et al. Characterization of melanocyte-specific inducible Cre recombinase transgenic mice. Genesis 44, 262–267 (2006).

    Article  CAS  Google Scholar 

  33. Hoek, K. S. et al. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment Cell Res. 19, 290–302 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the FACS facility and the Functional Genomic Center Zurich (FGCZ) of the University of Zurich for technical assistance, S. Behnke and C. Burger for assistance in histology, and M. Serrano and L. Chin for providing mouse lines. This work was supported by the Swiss Cancer League (including a grant supporting a Collaborative Cancer Research Project (CCRP) by D.M.P., R.D. and L.S.), the Swiss National Science Foundation, the National Research Program (NRP63) ‘Stem Cells and Regenerative Medicine’ and a stipend from the UBS Wealth Management.

Author information

Authors and Affiliations

  1. Cell and Developmental Biology, Institute of Anatomy, University of Zurich, CH-8057 Zurich, Winterthurerstrasse 190, Switzerland

    Olga Shakhova, Daniel Zingg, Simon M. Schaefer, Lisette Hari, Gianluca Civenni, Jacqueline Blunschi & Lukas Sommer

  2. Laboratory of Stem Cell Dynamics, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland

    Stéphanie Claudinot & Yann Barrandon

  3. Functional Genomics Center Zurich, CH-8057 Zurich, Winterthurerstrasse 190, Switzerland

    Michal Okoniewski

  4. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland

    Friedrich Beermann

  5. Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland

    Daniela Mihic-Probst & Holger Moch

  6. Institute for Biochemistry, Emil Fischer Center, University of Erlangen-Nuernberg, D-91054 Erlangen, Germany

    Michael Wegner

  7. Department of Dermatology, University Hospital Zurich, CH-8091 Zurich, Gloriastrasse 31, Switzerland

    Reinhard Dummer

  8. Institute of Laboratory Animal Science, University of Zurich, CH-8057 Zurich, Winterthurerstrasse 190, Switzerland

    Paolo Cinelli

  9. Center for Applied Biotechnology and Molecular Medicine, University of Zurich, CH-8057 Zurich, Winterthurerstrasse 190, Switzerland

    Paolo Cinelli

Authors
  1. Olga Shakhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Zingg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simon M. Schaefer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lisette Hari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gianluca Civenni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jacqueline Blunschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stéphanie Claudinot
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michal Okoniewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Friedrich Beermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniela Mihic-Probst
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Holger Moch
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michael Wegner
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Reinhard Dummer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yann Barrandon
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Paolo Cinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lukas Sommer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

O.S., P.C. and L.S. designed the experiments, O.S., P.C., D.Z., S.M.S., L.H., G.C., S.C. and J.B. performed the experiments, and O.S., P.C., M.O., D.M., R.D., Y.B., P.C. and L.S. analysed the data. R.D. provided human congenital naevus samples. D.M. and H.M. provided tissue microarrays of primary and metastatic melanoma samples. M.W. provided Sox10LacZ/+ and Sox10fl/+ mice. F.B. provided Tyr::NrasQ61K mice. O.S. and L.S. wrote the manuscript.

Corresponding authors

Correspondence to Olga Shakhova or Lukas Sommer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1486 kb)

Supplementary Table 1

Supplementary Information (XLSX 46 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shakhova, O., Zingg, D., Schaefer, S. et al. Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma. Nat Cell Biol 14, 882–890 (2012). https://doi.org/10.1038/ncb2535

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2535

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing