Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease
| العنوان: | Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease |
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| المؤلفون: | Eiríkur Steingrímsson, Ava Khamseh, Jana Travnickova, Colin A. Semple, Michaela Spitzer, Amy Capper, ME Mathers, Philippe Gautier, Chris P. Ponting, Ramile Dilshat, James A. Lister, Ailith Ewing, Alessandro Brombin, Sonia Wojciechowska, E. Elizabeth Patton, Daniel Brown, Thierry Voet, Thomas Lefevre |
| المصدر: | Travnickova, J, Wojciechowska, S, Khamseh, A, Gautier, P, Brown, D V, Lefevre, T, Brombin, A, Ewing, A, Capper, A, Spitzer, M, Dilshat, R, Semple, C A, Mathers, M E, Lister, J A, Steingrimsson, E, Voet, T, Ponting, C P & Patton, E E 2019, ' Zebrafish MITF-low melanoma subtype models reveal transcriptional subclusters and MITF-independent residual disease ', Cancer Research, vol. 79, no. 22, pp. 5769-5784 . https://doi.org/10.1158/0008-5472.CAN-19-0037Test Cancer Res Cancer Research |
| مصطلحات موضوعية: | Proto-Oncogene Proteins B-raf, 0301 basic medicine, Cancer Research, Neoplasm, Residual, Transcription, Genetic, Drug Resistance, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic model, medicine, Animals, Melanoma, Zebrafish, Regulation of gene expression, Microphthalmia-Associated Transcription Factor, biology, integumentary system, Gene Expression Profiling, Stem Cells, Neural crest, Microphthalmia-associated transcription factor, biology.organism_classification, medicine.disease, Minimal residual disease, Gene Expression Regulation, Neoplastic, body regions, 030104 developmental biology, Oncology, Neural Crest, 030220 oncology & carcinogenesis, Cancer research, Melanocytes, Neoplasm Recurrence, Local, Stem cell |
| الوصف: | 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 BRAFV600E 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 G0-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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-19-0037 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8f2239983694b5e18c7b41a6ddda0463Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8f2239983694b5e18c7b41a6ddda0463 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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| DOI: | 10.1158/0008-5472.can-19-0037 |