Emerging from the Field

Summary and Comment |
March 17, 2016

Emerging from the Field

  1. Kenneth Y. Tsai, MD, PhD

A zebrafish melanoma model shows the emergence of neural crest identity during melanoma initiation.

  1. Kenneth Y. Tsai, MD, PhD

The concept of field cancerization is well established, especially in skin. Essentially, fields of skin damage related usually to ultraviolet (UV) exposure have acquired DNA damage that primes them for cancer development. However, it is unclear why, given the swath of UV-damaged tissue, clones that give rise to cancer remain dramatically rare.

These researchers used a model of melanoma in which oncogenic BRAFV600E is expressed in melanocytes in zebrafish that lack P53. An additional twist here is that the protein crestin was linked to a green fluorescent protein, enabling all crestin-expressing cells to be visualized in vivo. Incredibly, rare clones of BRAFV600E-expressing melanocytes turned on crestin expression, thus re-expressing a neural crest program. By observing the animals across their development, they saw that crestin expression was confined to the embryo during neural crest development and then shut off, only to re-emerge in melanomas.

They then tracked down pieces of DNA that appeared to regulate crestin in this fashion, showing that SOX10 and PAX3 were important regulators of crestin expression. Indeed, removal of SOX10 delayed melanoma formation. Finally, by tracing transcriptional patterns regulated by histone modifications across the genome, they identified similarities in large-scale transcriptional drivers suggesting a close correspondence between human melanoma cell lines and neural crest progenitors.

Comment

This paper offers insight into events driving single cells within initiated fields, and how reactivation of key developmental programs are involved. In melanoma, neural crest progenitors are important, as are hair follicle progenitors in basal cell carcinoma. While this sheds light on the emergence of single clones, crestin has no human equivalent, so the mechanisms that drive early human melanomagenesis remain unclear. The next step will be to establish why and how specific cells initiate developmental progress that results in cancer.

Editor Disclosures at Time of Publication

  • Disclosures for Kenneth Y. Tsai, MD, PhD at time of publication Grant / Research support American Association for Cancer Research – Landon Foundation; National Institutes of Health/National Cancer Institute; Cancer Prevention Research Institute of Texas Editorial Boards Journal of the American Academy of Dermatology

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