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Mol Cell. 2015 Aug 20;59(4):664-76. doi: 10.1016/j.molcel.2015.06.028. Epub 2015 Jul 30.

Interactions of Melanoma Cells with Distal Keratinocytes Trigger Metastasis via Notch Signaling Inhibition of MITF.

Author information

1
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
2
Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
3
Department of Medicine, Center for Cancer Research, Tel Hashomer 52621, Israel.
4
Department of Dermatology, Sheba Medical Center, Tel Hashomer 52621, Israel.
5
Institut Gustave Roussy, INSERM U753, Villejuif 94805, France.
6
Nice Sophia Antipolis University, INSERM, U1081, CNRS, UMR7284, 06107 Nice, France.
7
Department of Developmental Biology and Cancer Research, The Hebrew University, Hadassah Medical School, Jerusalem 91120, Israel.
8
Department of Biochemistry and Molecular Biology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
9
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: carmitlevy@post.tau.ac.il.

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.

PMID:
26236014
DOI:
10.1016/j.molcel.2015.06.028
[Indexed for MEDLINE]
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