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Epigenetic Transdifferentiation of Normal Melanocytes by a Metastatic Melanoma Microenvironment

¹ Children's Memorial Research Center and Robert H. Lurie Comprehensive Cancer Center at Northwestern University; ² Department of Pathology, Loyola University of Chicago Medical Center, Chicago, Illinois; ³ Translational Genomics Research Institute, Phoenix, Arizona; ⁴ Dana-Farber Cancer Institute and Harvard Medical School; and ⁵ Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Mary J.C. Hendrix, Children's Memorial Research Center, 2300 Children's Plaza, Box 222, Chicago, IL 60614. Phone: 773-755-6528; Fax: 773-755-6594; E-mail: mjchendrix{at}childrensmemorial.org.

The clinical management of cutaneous melanoma would benefit significantly from a better understanding of the molecular changes that occur during melanocytic progression to a melanoma phenotype. To gain unique insights into this process, we developed a three-dimensional in vitro model that allows observations of normal human melanocytes interacting with a metastatic melanoma matrix to determine whether these normal cells could be reprogrammed by inductive cues in the tumor cell microenvironment. The results show the epigenetic transdifferentiation of the normal melanocytic phenotype to that of an aggressive melanoma-like cell with commensurate increased migratory and invasive ability with no detectable genomic alterations. Removal of the transdifferentiated melanocytes from the inductive metastatic melanoma microenvironment results in a reversion to their normal phenotype. However, a normal melanocyte microenvironment had no epigenetic influence on the phenotype of metastatic melanoma cells. This novel approach identifies specific genes involved in the transdifferentiation of melanocytes to a more aggressive phenotype, which may offer significant therapeutic value.

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