Zebrafish MITF-low melanoma subtype models reveal transcriptional subclusters and MITF-independent residual disease

Travnickova, J; Wojciechowska, S; Khamseh, A; Gautier, P; Brown, DV; Lefevre, T; Brombin, A; Ewing, A; Capper, A; Spitzer, M; Dilshat, R; Semple, CA; Mathers, ME; Lister, JA; Steingrimsson, E; Voet, T; Ponting, CP; Patton, EE

Author(s): Travnickova, J; Wojciechowska, S; Khamseh, A; Gautier, P; Brown, DV; Lefevre, T; Brombin, A; Ewing, A; Capper, A; Spitzer, M; Dilshat, R; Semple, CA; Mathers, ME; Lister, JA; Steingrimsson, E; Voet, T; Ponting, CP; Patton, EE;
Details: Publication Year 2019-11,Volume 79,Issue #22,Page 5769-5784
Journal Title: Cancer Research
Publication Type: Journal Article
Abstract: 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 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-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.
Publisher: AACR
Research Division(s): Advanced Technology And Biology
PubMed ID: 31582381
Publisher's Version: https://doi.org/10.1158/0008-5472.CAN-19-0037
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2019-10-23 02:22:55

Last Modified: 2019-12-03 09:17:49