Journal Article

MITF reprograms the extracellular matrix and focal adhesion in melanoma

Larue, Lionel, Ögmundsdóttir, Margrét Helga, Möller, Katrin, Dilshat, Ramile, Cornell, Robert A, Fock, Valerie, Patton, E Elizabeth, de Tayrac, Marie, Magnúsdóttir, Erna, Kenny, Colin, Travnickova, Jana, Lasseur, Romain Maurice Jacques, Sigurbjörnsdóttir, Sara, Kirty, Kritika, Steingrimsson, Eirikur, Eichhoff, Ossia M, Einarsdottir, Berglind Ósk, Gerritsen, Ilse, Levesque, Mitchell, Cerny, Philipp, Cheng, Phil F

2021

Overview

The microphthalmia-associated transcription factor (MITF) is a critical regulator of melanocyte development and differentiation. It also plays an important role in melanoma where it has been described as a molecular rheostat that, depending on activity levels, allows reversible switching between different cellular states. Here, we show that MITF directly represses the expression of genes associated with the extracellular matrix (ECM) and focal adhesion pathways in human melanoma cells as well as of regulators of epithelial-to-mesenchymal transition (EMT) such as CDH2, thus affecting cell morphology and cell-matrix interactions. Importantly, we show that these effects of MITF are reversible, as expected from the rheostat model. The number of focal adhesion points increased upon MITF knockdown, a feature observed in drug-resistant melanomas. Cells lacking MITF are similar to the cells of minimal residual disease observed in both human and zebrafish melanomas. Our results suggest that MITF plays a critical role as a repressor of gene expression and is actively involved in shaping the microenvironment of melanoma cells in a cell-autonomous manner.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publication,eLife Sciences Publications, Ltd
• Subject: Adhesion / Cancer Biology / Cell Line, Tumor / CRISPR / Cytology / Drug resistance / Epithelial-Mesenchymal Transition / Extracellular matrix / Extracellular Matrix - metabolism / focal adhesion / Focal Adhesions - metabolism / Gene expression / Genetic aspects / Genetics and Genomics / Genotype & phenotype / Humans / Kinases / Life Sciences / Medical prognosis / Melanoma / Melanoma - metabolism / Mesenchyme / Metastasis / Microenvironments / Microphthalmia-associated transcription factor / Microphthalmia-Associated Transcription Factor - genetics / Microphthalmia-Associated Transcription Factor - metabolism / Minimal residual disease / MITF / Mutation / Proteins / repression / Skin cancer / Tumors