Transcriptional regulators and alterations that drive melanoma initiation and progression.
Transcriptional regulators and alterations that drive melanoma initiation and progression.
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DOI：
10.1038/s41388-020-01490-x
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发表时间：
2020-11
期刊：
影响因子：
8
通讯作者：
Wajapeyee N
中科院分区：
文献类型：
--
作者：
Gupta R;Janostiak R;Wajapeyee N
尽管黑色素瘤是最不常见的皮肤癌类型，但它占皮肤癌相关死亡的大部分。大规模测序工作已将黑色素瘤分为四种主要亚型（即 BRAF 突变型、NRAS 突变型、NF1 缺陷型和三重野生型）。这些测序研究还表明，黑色素瘤基因组是所有癌症中突变最严重的基因组之一，因此具有很高的新抗原负载。这些发现促进了针对致癌 BRAF→MEK→ERK 通路的靶向疗法和用于治疗转移性黑色素瘤的免疫检查点抑制剂的开发和临床应用。尽管一些转移性黑色素瘤患者从这些变革性疗法中获益匪浅，但其他患者要么产生耐药性，要么根本没有反应。这些临床挑战加强了对新药物靶点和药物的寻找，这些靶点和药物可以使对靶向治疗和免疫疗法具有内在耐药性或获得耐药性的患者受益。许多信号通路和致癌驱动因素可引起 mRNA 转录的变化，进而驱动黑色素瘤的发生和进展。 mRNA 表达的转录调节对于通过转录因子表达和功能、启动子/增强子活性、染色质调节子和三维基因组组织的调节来维持细胞身份和细胞可塑性是必要的。转录失调可能是由于基因组中的遗传和/或非遗传改变而引起的。具体来说，这些解除管制的转录程序可能会成为黑色素瘤细胞的负担，因为它们对这些程序的生存依赖，可以用来开发黑色素瘤的新疗法。在本文中，我们概述了导致黑色素瘤细胞中 mRNA 表达转录失调的机制，并评估了这些变化如何促进黑色素瘤的发生和进展。我们还描述了这些失调的转录途径如何为开发非常规且具有潜在影响的转移性黑色素瘤治疗方法带来新的机遇。
Although melanoma is the least frequent type of skin cancer, it accounts for the majority of skin cancer-related deaths. Large-scale sequencing efforts have led to the classification of melanoma into four major subtypes (i.e., BRAF-mutant, NRAS-mutant, NF1-deficient, and triple wild-type). These sequencing studies have also revealed that melanoma genomes are some of the most mutated genomes of all cancers and therefore have a high neoantigen load. These findings have resulted in the development and clinical use of targeted therapies against the oncogenic BRAF→MEK→ERK pathway and immune checkpoint inhibitors for the treatment of metastatic melanoma. Although some patients with metastatic melanoma benefit immensely from these transformative therapies, others either become resistant or do not respond at all. These clinical challenges have intensified the search for new drug targets and drugs that can benefit patients who are either intrinsically resistant or have acquired resistance to targeted therapies and immunotherapies. Numerous signaling pathways and oncogenic drivers can cause changes in mRNA transcription that in turn drive melanoma initiation and progression. Transcriptional regulation of mRNA expression is necessary to maintain cell identity and cellular plasticity via the regulation of transcription factor expression and function, promoter/enhancer activities, chromatin regulators, and three-dimensional genome organization. Transcriptional deregulation can arise due to genetic and/or non-genetic alterations in the genome. Specifically, these deregulated transcriptional programs can become liabilities for melanoma cells due to their acquired dependencies on these programs for survival, which can be harnessed to develop new therapies for melanoma. In this article, we present an overview of the mechanisms that result in the transcriptional deregulation of mRNA expression in melanoma cells and assess how these changes facilitate melanoma initiation and progression. We also describe how these deregulated transcriptional pathways represent new opportunities for the development of unconventional and potentially impactful treatments for metastatic melanoma.
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影响因子：
13.6
作者：
Dai C;Gu W
通讯作者：
Gu W
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
ERK 介导的磷酸化调节 SOX10 sumoylation 并靶向突变 BRAF 黑色素瘤中的表达
影响因子：
16.6
作者：
Han S;Ren Y;He W;Liu H;Zhi Z;Zhu X;Yang T;Rong Y;Ma B;Purwin TJ;Ouyang Z;Li C;Wang X;Wang X;Yang H;Zheng Y;Aplin AE;Liu J;Shao Y
通讯作者：
Shao Y
影响因子：
5.3
作者：
Goodall, J;Wellbrock, C;Goding, CR
通讯作者：
Goding, CR
影响因子：
10.5
作者：
Herbert, Katharine;Binet, Romuald;Goding, Colin R.
通讯作者：
Goding, Colin R.