title: Notch signaling mediates melanoma-endothelial cell communication and melanoma cell migration.
abstract: 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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Howard
authors.forename: Whei F
authors.initials: WF
authors.lastname: Moriarty
authors.forename: JinSeok
authors.initials: J
authors.lastname: Park
authors.forename: Katherine
authors.initials: K
authors.lastname: Riedy
authors.forename: Izabela P
authors.initials: IP
authors.lastname: Panova
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: Kahp-Yang
authors.initials: KY
authors.lastname: Suh
authors.forename: Andre
authors.initials: A
authors.lastname: Levchenko
authors.forename: Rhoda M
authors.initials: RM
authors.lastname: Alani
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002450:Cell Communication; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009506:Nevus / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C485631:HEY1 protein, human; C499374:NOTCH3 protein, human
keywords: Notch3; endothelial cells; melanoma; tumormicroenvironment