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Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes

¹ Wistar Institute; ² University of Pennsylvania School of Medicine; Departments of ³ Medicine and ⁴ Pathology and Laboratory Medicine, Abramson Family Cancer Reseearch Institute, University of Pennsylvania, Philadephia, Pennsylvania; ⁵ Translational Genomics Research Institute, Phoenix, Arizona; ⁶ National Institute on Aging, NIH, Baltimore, Maryland; and ⁷ Department of Pathology, Loyola University Medical Center, Maywood, Illinois

Requests for reprints: Meenhard Herlyn, Wistar Institute, 3601 Spruce Street, Room 489, Philadelphia, PA 19104. Phone: 215-898-3950; Fax: 215-898-0980; E-mail: herlynm{at}wistar.org.

Key Words: Notch • melanoma • transformation • MCAM • therapy

The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (N^IC) was exploited to determine if Notch activation is a "driving" event in melanocytic transformation or instead a "passenger" event associated with melanoma progression. N^IC-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. N^IC-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease. [Cancer Res 2009;69(13):5312–20]