MITF reprograms the extracellular matrix and focal adhesion in melanoma
- University of Iceland, Iceland
- University of Iowa, United States
- University of Edinburgh, United Kingdom
- University Hospital Zurich, Switzerland
- Institut Curie, France
- Univ Rennes1, France
Abstract
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.
Data availability
MITF CUT&RUN sequencing data have been deposited in GEO under accession codes GSE153020 and the RNA-Seq data discussed in this publication are available under the accession number GSE163646.
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MITF ChIP-seq in primary melanocyte and melanoma as a function of oncogenic BRAFNCBI Gene Expression Omnibus, GSE50681.
Article and author information
Author details
Ossia Margarita Eichhoff
E Elizabeth Patton
Eirikur Steingrimsson
Funding
Icelandic Centre for Research (184861 and 767 207067)
- Eirikur Steingrimsson
National Institutes of Health (A2062457)
- Robert A Cornell
H2020 European Research Council (ZF-MEL-CHEMBIO-648489)
- E Elizabeth Patton
L'Oreal Melanoma Research Alliance (401181)
- E Elizabeth Patton
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Dilshat et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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MITF reprograms the extracellular matrix and focal adhesion in melanoma
eLife 10:e63093.
https://doi.org/10.7554/eLife.63093
Further reading
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- Cancer Biology
Background:
Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.
Methods:
We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.
Results:
Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.
Conclusions:
This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.
Funding:
Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).
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- Cancer Biology
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