Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease

Trávníčková, Jana; Wojciechowska, Sonia; Khamseh, Ava; Gautier, Philippe; Brown, Daniel V.; Lefevre, Thomas; Brombin, Alessandro; Ewing, Ailith; Capper, Amy; Spitzer, Michaela; Dilshat, Ramile; Semple, Colin A.; Mathers, Marie E.; Lister, James; Steingrímsson, Eiríkur; Voet, Thierry; Ponting, Chris P.; Patton, E. Elizabeth

doi:10.1158/0008-5472.can-19-0037

Cited by 44 publications

(102 citation statements)

References 54 publications

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“…Among the genes that overlap between the MRD and ∆MITF-X6 cells are ECM genes such as COL4A1, ITGA1, ITGA6, LAMC1 and VCAN. The same findings were obtained using single cell RNA-Seq data of MITF-depleted zebrafish melanomas as well as bulk-RNA-Seq data of MITFlow melanoma tumours [22]. Both datasets showed positive enrichment with ∆MITF-X6 cells ( Supplementary Fig.…”

Section: Mitf Affects the Number Of Focal Adhesionssupporting

confidence: 77%

“…Immunohistochemistry and single-cell sequencing studies of melanoma tumours have shown the existence of cells with low or no MITF expression [20][21][22]. The involvement of MITF in migration has mostly been characterized using knockdown studies in melanoma cell lines using either siRNA or shRNA and by using Matrigel-coated Boyden chambers [14,[44][45][46]; in these studies knocking down MITF resulted in increased migration properties.…”

Section: Discussionmentioning

confidence: 99%

“…Since MITF expression and activity are regulated by the various signalling pathways, the tumour microenvironment has been proposed to instruct phenotypic changes in melanoma cells and thus foster disease progression [16][17][18][19]. However, antibody staining suggests that cells lacking MITF are abundant in melanomas [20] and single-cell sequencing of human xenotransplants and of zebrafish melanoma models suggest the existence of cells with very low MITF expression [21,22]. These cells belong to a population of cells believed to represent minimal residual disease, cells that remain viable upon drug exposure.…”

Section: Introductionmentioning

confidence: 99%

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MITF reprograms the extracellular matrix and focal adhesion in melanoma

Dilshat

Fock

Kenny

et al. 2020

Preprint

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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.

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Section: Mitf Affects the Number Of Focal Adhesionssupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MITF reprograms the extracellular matrix and focal adhesion in melanoma

Dilshat

Fock

Kenny

et al. 2020

Preprint

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“…(D) Melanoma modifiers introduced into the Tg(mitfa:BRAF V600E ); p53(lf) model using MiniCoopR (MCR) resulted in aggressive melanomas, comparable to other models with alternative tumor drivers such as NRAS proto-oncogene, GTPase (NRAS Q61K ) or HRas proto-oncogene, GTPase (HRAS G12V ) [21,27,36,[45][46][47][48]. (E) Expression of HEXIM P-TEFb complex subunit 1 (HEXIM1) using MiniCoopR, or loss of growth differentiation factor 6 alpha (gdf6a) in a Tg(mitfa:BRAF V600E );p53(lf) background led to delayed melanoma onset [36,49].…”

Section: Using Zebrafish To Discover Genetic Modifiers Of Melanomamentioning

confidence: 88%

From Tank to Treatment: Modeling Melanoma in Zebrafish

Frantz

Ceol

2020

Cells

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Melanoma is the deadliest form of skin cancer and one of few cancers with a growing incidence. A thorough understanding of its pathogenesis is fundamental to developing new strategies to combat mortality and morbidity. Zebrafish—due in large part to their tractable genetics, conserved pathways, and optical properties—have emerged as an excellent system to model melanoma. Zebrafish have been used to study melanoma from a single tumor initiating cell, through metastasis, remission, and finally into relapse. In this review, we examine seminal zebrafish studies that have advanced our understanding of melanoma.

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“…Previous scRNA-Seq melanoma studies have revealed multiple cell states in melanoma, including neural crest, pigmented, invasive and starved states (Rambow et al, 2018) . We and others have previously shown that the neural crest transcriptional program, typified by genes such as SOX10 , is essential to melanoma initiation because it provides the proper mileu on which DNA mutations can act (Kaufman et al, 2016;Shakhova et al, 2012;Travnickova et al, 2019;White et al, 2011) . In contrast, the existence of other cell states such as a "stress-like" state, expressing genes such as fos and jun , has been suggested by prior work but its functional role remains unclear (Tirosh et al, 2016a) .…”

Section: Introductionmentioning

confidence: 99%

A population of stress-like cancer cells in melanoma promotes tumorigenesis and confers drug resistance

M¹,

Tagore

Hunter

et al. 2018

Preprint

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Transcriptional profiling has revealed a diverse range of cancer cell states, however an understanding of their function has remained elusive. Using a combination of zebrafish melanoma modeling and human validation, we have identified a conserved stress-like state that confers intrinsic drug resistance. The stress-like state expresses genes such as fos , hsp70 and ubb , all required for adaptation to diverse cellular stresses, and we confirmed its existence using immunofluorescence and spatial transcriptomics. We provide evidence that this state has a higher tumor seeding capabilities compared to non-stressed cells, and confers intrinsic resistance to MEK inhibitors, a commonly used melanoma therapeutic. Furthermore, the stress-like program can be induced by extrinsic processes such as heat shock, and confers resistance to both MEK and BRAF inhibitors in both zebrafish and human melanomas.Collectively, our study suggests that the transcriptional states associated with therapeutic failure are established during the earliest steps of tumorigenesis.

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Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease

Abstract: Zebrafish MITF-low melanoma models human MITF-low melanoma. While the bulk of the tumor is dependent on MITF activity, MITF-independent cells preexist and arise de novo in residual disease.

Cited by 44 publications

References 54 publications

MITF reprograms the extracellular matrix and focal adhesion in melanoma

MITF reprograms the extracellular matrix and focal adhesion in melanoma

From Tank to Treatment: Modeling Melanoma in Zebrafish

A population of stress-like cancer cells in melanoma promotes tumorigenesis and confers drug resistance

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