Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease
The melanocyte-inducing transcription factor (MITF)-low melanoma transcriptional signature is predictive of poor outcomes for patients, but little is known about its biological significance, and animal models are lacking. Here, we used zebrafish genetic models with low activity of Mitfa (MITF-low) a...
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Published in | Cancer research (Chicago, Ill.) Vol. 79; no. 22; pp. 5769 - 5784 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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15.11.2019
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Abstract | The melanocyte-inducing transcription factor (MITF)-low melanoma transcriptional signature is predictive of poor outcomes for patients, but little is known about its biological significance, and animal models are lacking. Here, we used zebrafish genetic models with low activity of Mitfa (MITF-low) and established that the MITF-low state is causal of melanoma progression and a predictor of melanoma biological subtype. MITF-low zebrafish melanomas resembled human MITF-low melanomas and were enriched for stem and invasive (mesenchymal) gene signatures. MITF-low activity coupled with a p53 mutation was sufficient to promote superficial growth melanomas, whereas BRAF
accelerated MITF-low melanoma onset and further promoted the development of MITF-high nodular growth melanomas. Genetic inhibition of MITF activity led to rapid regression; recurrence occurred following reactivation of MITF. At the regression site, there was minimal residual disease that was resistant to loss of MITF activity (termed MITF-independent cells) with very low-to-no MITF activity or protein. Transcriptomic analysis of MITF-independent residual disease showed enrichment of mesenchymal and neural crest stem cell signatures similar to human therapy-resistant melanomas. Single-cell RNA sequencing revealed MITF-independent residual disease was heterogeneous depending on melanoma subtype. Further, there was a shared subpopulation of residual disease cells that was enriched for a neural crest G
-like state that preexisted in the primary tumor and remained present in recurring melanomas. These findings suggest that invasive and stem-like programs coupled with cellular heterogeneity contribute to poor outcomes for MITF-low melanoma patients and that MITF-independent subpopulations are an important therapeutic target to achieve long-term survival outcomes. SIGNIFICANCE: This study provides a useful model for MITF-low melanomas and MITF-independent cell populations that can be used to study the mechanisms that drive these tumors as well as identify potential therapeutic options.
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AbstractList | The MITF-low melanoma transcriptional signature is predictive of poor outcomes for patients but little is known about its biological significance and animal models are lacking. Here, we used zebrafish genetic models with low activity of Mitfa (MITF-low) and established that the MITF-low state is causal of melanoma progression and a predictor of melanoma biological subtype. MITF-low zebrafish melanomas resembled human MITF-low melanomas and were enriched for stem and invasive (mesenchymal) gene signatures. MITF-low activity coupled with a p53 mutation was sufficient to promote superficial growth melanomas, while BRAF
V600E
accelerated MITF-low melanoma onset and further promoted the development of MITF-high nodular growth melanomas. Genetic inhibition of MITF activity led to rapid regression; recurrence occurred following reactivation of MITF. At the regression site, there was minimal residual disease that was resistant to loss of MITF activity (termed MITF-independent cells) with very low-to-no MITF activity or protein. Transcriptomic analysis of MITF-independent residual disease showed enrichment of mesenchymal and neural crest stem cell signatures similar to human therapy-resistant melanomas. Single-cell RNA-seq revealed MITF-independent residual disease was heterogeneous depending on melanoma subtype. Further, there was a shared subpopulation of residual disease cells that was enriched for a neural crest G0-like state that pre-existed in the primary tumor and remained present in recurring melanomas. These findings suggest that invasive and stem-like programs coupled with cellular heterogeneity contribute to poor outcomes for MITF-low melanoma patients, and that MITF-independent subpopulations are an important therapeutic target to achieve long-term survival outcomes. The melanocyte-inducing transcription factor (MITF)-low melanoma transcriptional signature is predictive of poor outcomes for patients, but little is known about its biological significance, and animal models are lacking. Here, we used zebrafish genetic models with low activity of Mitfa (MITF-low) and established that the MITF-low state is causal of melanoma progression and a predictor of melanoma biological subtype. MITF-low zebrafish melanomas resembled human MITF-low melanomas and were enriched for stem and invasive (mesenchymal) gene signatures. MITF-low activity coupled with a p53 mutation was sufficient to promote superficial growth melanomas, whereas BRAF accelerated MITF-low melanoma onset and further promoted the development of MITF-high nodular growth melanomas. Genetic inhibition of MITF activity led to rapid regression; recurrence occurred following reactivation of MITF. At the regression site, there was minimal residual disease that was resistant to loss of MITF activity (termed MITF-independent cells) with very low-to-no MITF activity or protein. Transcriptomic analysis of MITF-independent residual disease showed enrichment of mesenchymal and neural crest stem cell signatures similar to human therapy-resistant melanomas. Single-cell RNA sequencing revealed MITF-independent residual disease was heterogeneous depending on melanoma subtype. Further, there was a shared subpopulation of residual disease cells that was enriched for a neural crest G -like state that preexisted in the primary tumor and remained present in recurring melanomas. These findings suggest that invasive and stem-like programs coupled with cellular heterogeneity contribute to poor outcomes for MITF-low melanoma patients and that MITF-independent subpopulations are an important therapeutic target to achieve long-term survival outcomes. SIGNIFICANCE: This study provides a useful model for MITF-low melanomas and MITF-independent cell populations that can be used to study the mechanisms that drive these tumors as well as identify potential therapeutic options. http://cancerres.aacrjournals.org/content/canres/79/22/5769/F1.large.jpg. |
Author | Spitzer, Michaela Dilshat, Ramile Mathers, Marie E Lefevre, Thomas Patton, E Elizabeth Travnickova, Jana Khamseh, Ava Capper, Amy Ewing, Ailith Semple, Colin A Lister, James A Steingrimsson, Eiríkur Wojciechowska, Sonia Ponting, Chris P Brown, Daniel V Voet, Thierry Gautier, Philippe Brombin, Alessandro |
AuthorAffiliation | 4 Department of Human Genetics, University of Leuven, KU Leuven, Leuven, 3000, Belgium 5 Immunology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Australia 7 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland 8 Department of Pathology, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK 10 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK 2 CRUK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK 1 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK 6 Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK. European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK 9 Department of Human and Molecular |
AuthorAffiliation_xml | – name: 1 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK – name: 2 CRUK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK – name: 8 Department of Pathology, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK – name: 3 Higgs Centre for Particle Physics, School of Physics & Astronomy, University of Edinburgh, Edinburgh EH9 3FD, United Kingdom – name: 9 Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA – name: 5 Immunology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Australia – name: 10 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK – name: 6 Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK. European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK – name: 7 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland – name: 4 Department of Human Genetics, University of Leuven, KU Leuven, Leuven, 3000, Belgium |
Author_xml | – sequence: 1 givenname: Jana orcidid: 0000-0002-8339-9162 surname: Travnickova fullname: Travnickova, Jana organization: CRUK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom – sequence: 2 givenname: Sonia orcidid: 0000-0002-1162-3700 surname: Wojciechowska fullname: Wojciechowska, Sonia organization: CRUK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom – sequence: 3 givenname: Ava orcidid: 0000-0001-5203-2205 surname: Khamseh fullname: Khamseh, Ava organization: Higgs Centre for Theoretical Physics, School of Physics and Astronomy, University of Edinburgh, Edinburgh, United Kingdom – sequence: 4 givenname: Philippe surname: Gautier fullname: Gautier, Philippe organization: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom – sequence: 5 givenname: Daniel V orcidid: 0000-0002-3594-5851 surname: Brown fullname: Brown, Daniel V organization: Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia – sequence: 6 givenname: Thomas surname: Lefevre fullname: Lefevre, Thomas organization: Department of Human Genetics, University of Leuven, KU Leuven, Leuven, Belgium – sequence: 7 givenname: Alessandro orcidid: 0000-0001-8262-9248 surname: Brombin fullname: Brombin, Alessandro organization: CRUK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom – sequence: 8 givenname: Ailith surname: Ewing fullname: Ewing, Ailith organization: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom – sequence: 9 givenname: Amy surname: Capper fullname: Capper, Amy organization: CRUK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom – sequence: 10 givenname: Michaela surname: Spitzer fullname: Spitzer, Michaela organization: Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom; and European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom – sequence: 11 givenname: Ramile surname: Dilshat fullname: Dilshat, Ramile organization: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland – sequence: 12 givenname: Colin A surname: Semple fullname: Semple, Colin A organization: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom – sequence: 13 givenname: Marie E surname: Mathers fullname: Mathers, Marie E organization: Department of Pathology, Western General Hospital, Edinburgh, United Kingdom – sequence: 14 givenname: James A orcidid: 0000-0002-8505-6710 surname: Lister fullname: Lister, James A organization: Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia – sequence: 15 givenname: Eiríkur surname: Steingrimsson fullname: Steingrimsson, Eiríkur organization: Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland – sequence: 16 givenname: Thierry surname: Voet fullname: Voet, Thierry organization: Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom – sequence: 17 givenname: Chris P surname: Ponting fullname: Ponting, Chris P organization: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom – sequence: 18 givenname: E Elizabeth surname: Patton fullname: Patton, E Elizabeth email: e.patton@igmm.ed.ac.uk organization: CRUK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom |
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Snippet | The melanocyte-inducing transcription factor (MITF)-low melanoma transcriptional signature is predictive of poor outcomes for patients, but little is known... The MITF-low melanoma transcriptional signature is predictive of poor outcomes for patients but little is known about its biological significance and animal... |
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SubjectTerms | Animals Drug Resistance - genetics Gene Expression Profiling - methods Gene Expression Regulation, Neoplastic - genetics Melanocytes - pathology Melanoma - genetics Melanoma - pathology Microphthalmia-Associated Transcription Factor - genetics Neoplasm Recurrence, Local - genetics Neoplasm Recurrence, Local - pathology Neoplasm, Residual - genetics Neoplasm, Residual - pathology Neural Crest - pathology Proto-Oncogene Proteins B-raf - genetics Stem Cells - pathology Transcription, Genetic - genetics Zebrafish - genetics |
Title | Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease |
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