Notch signaling mediates melanoma-endothelial cell communication and melanoma cell migration

• Published in: Pigment cell and melanoma research 2013-09, Vol.26 (5), p.697-707
• Main Authors: Howard, Jason D., Moriarty, Whei F., Park, JinSeok, Riedy, Katherine, Panova, Izabela P., Chung, Christine H., Suh, Kahp-Yang, Levchenko, Andre, Alani, Rhoda M.
• Format: Article
• Language: English
• Subjects: Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell adhesion & migration; Cell Communication; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coculture Techniques; Communication; endothelial cells; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Neoplasm Invasiveness; Nevus - metabolism; Nevus - pathology; Notch3; Receptor, Notch3; Receptors, Notch - genetics; Receptors, Notch - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - genetics; tumormicroenvironment; Tumors; Up-Regulation
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12131

Summary Stromal and cellular components within the tumor microenvironment significantly influence molecular signals mediating tumor growth and progression. We recently performed a screen to evaluate critical mediators of melanoma–endothelial communication and identified several molecular pathways associated with these cellular networks, including Notch3. Here, we evaluate the nature of melanoma–endothelial communication mediated by Notch3 and its functional significance. We find that Notch3 is specifically upregulated in melanoma–endothelial cell cocultures and is functionally associated with increased Notch signaling in melanoma cells. Furthermore, induced Notch3 signaling in melanoma cell lines leads to enhanced tumor cell migration without associated increases in tumor cell growth. Additionally, Notch3 expression is specifically associated with malignant patient samples and is not evident in benign nevi. We conclude that Notch3 mediates melanoma–endothelial cell communication and tumor cell migration and may serve as a meaningful therapeutic target for this aggressive malignancy.