title: Interactions of Melanoma Cells with Distal Keratinocytes Trigger Metastasis via Notch Signaling Inhibition of MITF.
abstract: The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We suggest that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR-222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR-222/221 promoter. This de-repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct melanoma prevention opportunities via targeting specific microenvironments.
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Golan
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Arielle R
authors.initials: AR
authors.lastname: Messer
authors.affiliation: Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Aya
authors.initials: A
authors.lastname: Amitai-Lange
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Melamed
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Reut
authors.initials: R
authors.lastname: Ohana
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Bell
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Oxana
authors.initials: O
authors.lastname: Kapitansky
authors.affiliation: Department of Medicine, Center for Cancer Research, Tel Hashomer 52621, Israel.
authors.forename: Galya
authors.initials: G
authors.lastname: Lerman
authors.affiliation: Department of Dermatology, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Greenberger
authors.affiliation: Institut Gustave Roussy, INSERM U753, Villejuif 94805, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khaled
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Nira
authors.initials: N
authors.lastname: Amar
authors.affiliation: Nice Sophia Antipolis University, INSERM, U1081, CNRS, UMR7284, 06107 Nice, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Albrengues
authors.affiliation: Nice Sophia Antipolis University, INSERM, U1081, CNRS, UMR7284, 06107 Nice, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Gaggioli
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Pinchas
authors.initials: P
authors.lastname: Gonen
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University, Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Tabach
authors.affiliation: Department of Biochemistry and Molecular Biology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Sprinzak
authors.affiliation: Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Ruby
authors.initials: R
authors.lastname: Shalom-Feuerstein
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: carmitlevy@post.tau.ac.il.
authors.forename: Carmit
authors.initials: C
authors.lastname: Levy
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002450:Cell Communication; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic; D015603:Keratinocytes / Q000502:physiology*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000556:secondary*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor; D051880:Receptors, Notch; C525709:MIR221, human; C525710:MIR222, human; C497234:MITF protein, human