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.

Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools

“…Thus, it has been shown that MITF interferes with production of MT1-MMP (19) or transcriptional activation of miR222/221 (42), a microRNA that is capable of invasion initiation in melanoma cells (43). Additionally, two papers reported different pathways through which MITF suppresses the activity of Rho-associated coiled-coil containing protein kinase 1 (ROCK1) (19, 20), an important regulator of tumor cell invasion (44) acting downstream of small GTPase RHO-A.…”

Enhancer methylation dynamics contribute to cancer plasticity and patient mortality

“…4D). Remarkably, noninvasive melanoma cells (Golan et al 2015) acquired significant invasion ability upon KIT overexpression ( Fig. 4G; Supplemental Fig.…”

“…Fortyeight hours post-transfection, an invasion assay was performed as previously described (Golan et al 2015).…”

The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology

“…51 MITF recruits RBPJK as a cofactor in repressing transcription of microRNAs miR-221 and miR-222 in human melanoma cell lines. 52 It remains mechanistically unclear how MITF represses target genes and what functional roles MITF has through repressing gene expression.…”