Microenvironment-Driven Dynamic Heterogeneity and Phenotypic Plasticity as a Mechanism of Melanoma Therapy Resistance.
Microenvironment-Driven Dynamic Heterogeneity and Phenotypic Plasticity as a Mechanism of Melanoma Therapy Resistance.
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DOI：
10.3389/fonc.2018.00173
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发表时间：
2018
影响因子：
4.7
通讯作者：
Haass NK
中科院分区：
文献类型：
--
作者：
Ahmed F;Haass NK
耐药性构成了设计黑色素瘤疗法的主要挑战。微环境驱动的肿瘤异质性和可塑性在这一现象中起着关键作用。黑色素瘤是高度异质性的，具有不同的基因组改变和不同生物标记物的表达。此外，黑色素瘤细胞具有高度可塑性，能够快速适应不断变化的微环境条件。这些导致个体黑色素瘤患者之间治疗反应和持久性的差异。为了应对不断变化的微环境条件，如缺氧和营养饥饿，增殖性黑色素瘤细胞可以切换到侵入性慢循环状态。这种状态下的细胞更具侵略性和转移性，并显示出增加的内在耐药性。在连续治疗期间，慢循环细胞在肿瘤内富集，并通过发挥其干细胞样行为和表型可塑性产生具有增加的耐药性的新增殖亚群。在黑色素瘤中，增殖和侵袭状态分别由高和低小眼相关转录因子（MITF）表达定义。已经观察到，在MITF高黑色素瘤中，MITF的抑制增加靶向疗法的功效并延迟耐药性的获得。首先，MITF在具有获得性耐药性的黑素瘤中下调。根据表型转换理论，MITFlow状态的基因表达谱主要受WNT 5A、AXL和NF-κB信号转导调节。因此，不同的治疗组合应该在治疗黑素瘤的不同阶段中有效，例如在初始治疗阶段期间靶向治疗与MITF表达抑制剂的组合，但在复发期间与WNT 5A/AXL/NF-κB信号传导抑制剂的组合。
Drug resistance constitutes a major challenge in designing melanoma therapies. Microenvironment-driven tumor heterogeneity and plasticity play a key role in this phenomenon. Melanoma is highly heterogeneous with diverse genomic alterations and expression of different biological markers. In addition, melanoma cells are highly plastic and capable of adapting quickly to changing microenvironmental conditions. These contribute to variations in therapy response and durability between individual melanoma patients. In response to changing microenvironmental conditions, like hypoxia and nutrient starvation, proliferative melanoma cells can switch to an invasive slow-cycling state. Cells in this state are more aggressive and metastatic, and show increased intrinsic drug resistance. During continuous treatment, slow-cycling cells are enriched within the tumor and give rise to a new proliferative subpopulation with increased drug resistance, by exerting their stem cell-like behavior and phenotypic plasticity. In melanoma, the proliferative and invasive states are defined by high and low microphthalmia-associated transcription factor (MITF) expression, respectively. It has been observed that in MITFhigh melanomas, inhibition of MITF increases the efficacy of targeted therapies and delays the acquisition of drug resistance. Contrarily, MITF is downregulated in melanomas with acquired drug resistance. According to the phenotype switching theory, the gene expression profile of the MITFlow state is predominantly regulated by WNT5A, AXL, and NF-κB signaling. Thus, different combinations of therapies should be effective in treating different phases of melanoma, such as the combination of targeted therapies with inhibitors of MITF expression during the initial treatment phase, but with inhibitors of WNT5A/AXL/NF-κB signaling during relapse.
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影响因子：
11.2
作者：
Gray-Schopfer, Vanessa C.;Karasarides, Maria;Marais, Richard
通讯作者：
Marais, Richard
影响因子：
82.9
作者：
Andor N;Graham TA;Jansen M;Xia LC;Aktipis CA;Petritsch C;Ji HP;Maley CC
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Maley CC
影响因子：
1.2
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Beaumont, Kimberley A.;Anfosso, Andrea;Haass, Nikolas K.
通讯作者：
Haass, Nikolas K.
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11.1
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Fane ME;Chhabra Y;Hollingsworth DEJ;Simmons JL;Spoerri L;Oh TG;Chauhan J;Chin T;Harris L;Harvey TJ;Muscat GEO;Goding CR;Sturm RA;Haass NK;Boyle GM;Piper M;Smith AG
通讯作者：
Smith AG
影响因子：
11.2
作者：
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通讯作者：
Bertolotto, Corine