Active Notch1 confers a transformed phenotype to primary human melanocytes

Chelsea C. Pinnix, John T. Lee, Zhao-Jun Liu, Ronan McDaid, Klara Balint, Levi J. Beverly, Patricia A. Brafford, Min Xiao, Benjamin Himes, Susan E. Zabierowski, Yumi Yashiro-Ohtani, Katherine L. Nathanson, Ana Bengston, Pamela M. Pollock, Ashani T. Weeraratna, Brian J. Nickoloff, Warren S. Pear, Anthony J Capobianco, Meenhard Herlyn

Research output: Contribution to journalArticle

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Abstract

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 (NIC) 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. NIC-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.

Original languageEnglish
Pages (from-to)5312-5320
Number of pages9
JournalCancer Research
Volume69
Issue number13
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

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Melanocytes
Melanoma
Phenotype
Oncogenes
Mitogen-Activated Protein Kinases
Transgenes
Cell Adhesion
Transcriptional Activation
Cell Movement
Epidemiology
Gene Expression
Cell Line
Mutation
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pinnix, C. C., Lee, J. T., Liu, Z-J., McDaid, R., Balint, K., Beverly, L. J., ... Herlyn, M. (2009). Active Notch1 confers a transformed phenotype to primary human melanocytes. Cancer Research, 69(13), 5312-5320. https://doi.org/10.1158/0008-5472.CAN-08-3767

Active Notch1 confers a transformed phenotype to primary human melanocytes. / Pinnix, Chelsea C.; Lee, John T.; Liu, Zhao-Jun; McDaid, Ronan; Balint, Klara; Beverly, Levi J.; Brafford, Patricia A.; Xiao, Min; Himes, Benjamin; Zabierowski, Susan E.; Yashiro-Ohtani, Yumi; Nathanson, Katherine L.; Bengston, Ana; Pollock, Pamela M.; Weeraratna, Ashani T.; Nickoloff, Brian J.; Pear, Warren S.; Capobianco, Anthony J; Herlyn, Meenhard.

In: Cancer Research, Vol. 69, No. 13, 01.07.2009, p. 5312-5320.

Research output: Contribution to journalArticle

Pinnix, CC, Lee, JT, Liu, Z-J, McDaid, R, Balint, K, Beverly, LJ, Brafford, PA, Xiao, M, Himes, B, Zabierowski, SE, Yashiro-Ohtani, Y, Nathanson, KL, Bengston, A, Pollock, PM, Weeraratna, AT, Nickoloff, BJ, Pear, WS, Capobianco, AJ & Herlyn, M 2009, 'Active Notch1 confers a transformed phenotype to primary human melanocytes', Cancer Research, vol. 69, no. 13, pp. 5312-5320. https://doi.org/10.1158/0008-5472.CAN-08-3767
Pinnix, Chelsea C. ; Lee, John T. ; Liu, Zhao-Jun ; McDaid, Ronan ; Balint, Klara ; Beverly, Levi J. ; Brafford, Patricia A. ; Xiao, Min ; Himes, Benjamin ; Zabierowski, Susan E. ; Yashiro-Ohtani, Yumi ; Nathanson, Katherine L. ; Bengston, Ana ; Pollock, Pamela M. ; Weeraratna, Ashani T. ; Nickoloff, Brian J. ; Pear, Warren S. ; Capobianco, Anthony J ; Herlyn, Meenhard. / Active Notch1 confers a transformed phenotype to primary human melanocytes. In: Cancer Research. 2009 ; Vol. 69, No. 13. pp. 5312-5320.
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