Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease.
Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease.
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斑马鱼 MITF 低黑色素瘤亚型模型揭示转录亚簇和 MITF 独立的残留疾病。
DOI：
10.1158/0008-5472.can-19-0037
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发表时间：
2019
期刊：
影响因子：
11.2
通讯作者：
Travnickova J
中科院分区：
文献类型：
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作者：
Travnickova J
黑素细胞诱导转录因子(MITF)-低黑色素瘤转录标志预示着患者的不良预后，但对其生物学意义知之甚少，也缺乏动物模型。在这里，我们使用了MITF低活性斑马鱼遗传模型(MITF-LOW)，并确定MITF-Low状态是黑色素瘤进展的原因和黑色素瘤生物学亚型的预测因子。MITF-Low斑马鱼黑色素瘤类似于人类MITF-Low黑色素瘤，富含茎和侵袭性(间充质)基因特征。MITF-低活性加上P53突变足以促进浅表黑色素瘤的发生，而BRAFV600E则加速了MITF-低黑色素瘤的发病，并进一步促进了MITF-高结节状生长黑色素瘤的发展。MITF活性的遗传抑制导致快速消退；MITF重新激活后复发。在退化点，存在抵抗MITF活性丧失的微小残留病(称为MITF非依赖性细胞)，其MITF活性或蛋白质非常低或没有。对MITF非依赖性残留病的转录分析显示，间充质干细胞和神经脊干细胞特征丰富，类似于人类耐药黑色素瘤。单细胞RNA测序显示，MITF非依赖性残留病变根据黑色素瘤亚型的不同而不同。此外，有一个共享的残留疾病细胞亚群，它被浓缩为神经峰样G0状态，这种状态在原发肿瘤中先前存在，在复发的黑色素瘤中仍然存在。这些发现表明，侵袭性和干细胞性方案加上细胞异质性导致MITF低黑色素瘤患者的不良预后，MITF非依赖性亚群是实现长期生存结果的重要治疗目标。意义本研究为MITF低黑色素瘤和MITF非依赖性细胞群提供了一个有用的模型，可用于研究驱动这些肿瘤的机制以及确定潜在的治疗方案。
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 BRAFV600Eaccelerated 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.SignificanceThis 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.