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Bmal1对黑色素瘤免疫力和瘤发生性的细胞状态依赖性影响

Xue Zhang^1,2,3, Shishir M Pant^4,5,6, Cecily C Ritch^4,5,7

¹The Wistar Institute, Philadelphia, PA, USA. xzhan325@jh.edu.

Nature communications

|January 20, 2024

概括

生物钟蛋白Bmal1对黑色素瘤的生长有不同的影响,取决于它的水平. 失去Bmal1会阻碍瘤生长,而过多的Bmal1会促进免疫抵抗和介质细胞状态.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
时间生物学时间生物学

背景情况:

生物钟调节器Bmal1 (大脑和肌肉ARNT-Like蛋白1) 已报告,但在瘤发生中的作用不一致.
了解Bmal1的上下文依赖功能对于癌症研究至关重要.

研究的目的:

研究Bmal1在小鼠黑色素瘤瘤生长中的上下文依赖作用.
阐明Bmal1对黑色素瘤细胞可塑性和免疫逃避的影响的分子机制.

主要方法:

利用了Bmal1功能丧失和过度表达的小鼠黑色素瘤细胞系 (YUMM2.1和B16-F10).
评估了瘤生长,基因表达 (低氧和AP-1签名) 和细胞状态过渡 (Sox10/Sox9).
研究了Bmal1,髓重链9 (Myh9) 和MRTF-SRF通路之间的相互作用.

主要成果:

黑色素瘤细胞中的Bmal1损失减少了瘤生长和缺氧基因表达,HIF1α部分挽救了这些效应.
过度表达Bmal1,包括一个转录不活跃的突变体,导致非正规的Myh9隔离.
这导致MRTF-SRF活性增加,AP-1转录特征,并转移到Sox9高,免疫抵抗性介质细胞状态.

结论:

Bmal1在黑色素瘤中表现出上下文依赖的作用,影响瘤生长和细胞可塑性.
在Bmal1,Myh9,细胞骨调节 (MRTF-SRF) 和黑色素瘤细胞状态可塑性之间存在一种新的联系.
这一途径可能有助于癌症的治疗耐药性,并突出了昼夜钟与癌症细胞骨之间的联系.

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