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

Tamar Golan, Arielle R. Messer, Aya Amitai-Lange, Ze'ev Melamed, Reut Ohana, Rachel E. Bell, Oxana Kapitansky, Galya Lerman, Shoshana Greenberger, Mehdi Khaled, Nira Amar, Jean Albrengues, Cedric Gaggioli, Pinchas Gonen, Yuval Tabach, David Sprinzak, Ruby Shalom-Feuerstein, Carmit Levy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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.

Original languageEnglish
Pages (from-to)664-676
Number of pages13
JournalMolecular Cell
Issue number4
StatePublished - 20 Aug 2015


FundersFunder number
Fingerhot Carol and Lionara Fund
I-CORE Gene Regulation in Complex Human Disease41/11
Yuval Levy for big joy
Israel Cancer Research Fund
Fritz Thyssen Stiftung
Israel Cancer Association


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