Role of nodal signaling and the microenvironment underlying melanoma plasticity

Authors

  • Lynne-Marie Postovit,

    Corresponding author
    1. Children’s Memorial Research Center, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University’s Feinberg School of Medicine, Chicago, IL, USA
    2. Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
      *Address correspondence to Lynne-Marie Postovit, e-mail: lynne.postovit@schulich.uwo.ca or Mary Hendrix, e-mail: mjchendrix@childrensmemorial.org
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  • Naira V. Margaryan,

    1. Children’s Memorial Research Center, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University’s Feinberg School of Medicine, Chicago, IL, USA
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  • Elisabeth A. Seftor,

    1. Children’s Memorial Research Center, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University’s Feinberg School of Medicine, Chicago, IL, USA
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  • Mary J. C. Hendrix

    1. Children’s Memorial Research Center, Cancer Biology and Epigenomics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University’s Feinberg School of Medicine, Chicago, IL, USA
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*Address correspondence to Lynne-Marie Postovit, e-mail: lynne.postovit@schulich.uwo.ca or Mary Hendrix, e-mail: mjchendrix@childrensmemorial.org

Abstract

The incidence of melanoma has increased dramatically over the last 50 yr, and although melanoma accounts for only 10% of all skin cancers, it is responsible for over 80% of skin cancer deaths. Recent studies have uncovered critical molecular events underlying melanocytic transformation and melanomagenesis. Among these noteworthy observations are the acquisition of stem cell-associated proteins, such as the Notch receptors and Nodal, which have also been implicated in melanoma progression. For example, we have demonstrated that Nodal expression is limited to invasive vertical growth phase and metastatic melanoma lesions, and that inhibition of Nodal signaling promotes the reversion of metastatic melanoma cells toward a more differentiated, less invasive non-tumorigenic phenotype. In addition, molecular cross-talk exists between the Notch and Nodal signaling pathways. Interestingly, the acquisition of stem cell-associated plasticity is often acquired via epigenetic mechanisms, and is therefore receptive to reprogramming in response to embryonic microenvironments. Here, we review the concept of melanoma plasticity, with an emphasis on the emerging role of Nodal as a regulator of melanoma tumorigenesis and progression, and present findings related to epigenetic reprogramming.

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