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通过组装致癌信号枢纽,促进细胞存活

Andrew D Weems¹, Erik S Welf^2,3, Meghan K Driscoll^2,4

¹Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA. Andrew.Weems@UTSouthwestern.edu.

|March 1, 2023

概括

细胞突起,小的膜突起,形成信号枢纽, 赋予癌细胞抗抗阿诺基, 这一发现揭示了癌症进展的新生存机制.

科学领域:

细胞生物学
癌症研究
分子信号

背景情况:

细胞的存活通常需要粘附于基质,脱离导致无菌 (编程细胞死亡).
癌细胞通常通过采用圆形形态和形成等离子体膜斑块来获得anoikis耐药性,这是转移的关键步骤.
在非迁移性环境中,尤其是的抗性,的确切功能仍未得到充分研究.

研究的目的:

调查血斑在赋予虫耐药性的作用.
阐明血栓在分离状态下促进细胞生存的分子机制.
探索在癌症中向血中介信号的治疗潜力.

主要方法:

三维成像和细胞形态状态的操纵.
分析信号通路的激活 (ERK,PI3K,MAPK) 作为反应.
研究 septin 蛋白和突变的 NRAS 在血栓相关的信号中心中的作用.
在脱离的癌细胞和纤维细胞中抑制血栓和隔膜的药理学.
评估BRAF和MEK抑制对血依赖生存的影响.

主要成果:

在血上诱导信号中心的形成, 招募隔膜以支架活跃的突变NRAS及其效应器.
这些信号枢纽激活ERK和PI3K通路,促进支持生存的信号.
在脱离的细胞中抑制血栓或隔膜会导致NRAS错位,减少MAPK/ PI3K活性和细胞死亡.
在结合BRAF和MEK阻断后,BRAF突变的黑色素瘤细胞对bleb/septin抑制变得敏感.
经过工程改造的纤维细胞表现出与癌细胞相似的耐药性,即使没有致癌突变.

结论:

通过组织支持生存的途径, 血细胞作为信号器官提供耐药性.
对于突变NRAS的致癌功能来说,Blebbing非常重要.
向血介导信号为癌症提供了潜在的治疗策略,特别是在组合治疗中.
这表明它们在细胞存活中起着重要的作用.

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