通过高含量查识别的细胞外矩阵内部化的新激酶调节剂调节侵入性癌细胞迁移
Montserrat Llanses Martinez1,2, Keqian Nan1, Zhe Bao1
1School of Biosciences, University of Sheffield, Western Bank, Sheffield, United Kingdom.
PLoS biology
|December 12, 2024
概括
这项研究揭示了癌细胞通过巨细胞结合体 (macropinocytosis) 内化细胞外基质 (ECM),由α2β1整合素/p38信号轴调节. 这一过程对于瘤细胞迁移,入侵和癌症患者的不良预后至关重要.
科学领域:
- 细胞生物学 细胞生物学
- 癌症研究 癌症研究
- 分子生物学分子生物学
背景情况:
- 细胞外基质 (ECM) 降解是瘤进展的关键,但ECM内细胞分裂的作用尚不清楚.
- 侵袭性乳腺癌细胞显示增加了ECM内部化,这表明与侵袭性有关.
- 现有的高通量方法在研究二维文化的ECM动态方面是有限的.
研究的目的:
- 开发一种高含量查试验,用于研究活癌细胞的ECM吸收和贩运.
- 确定ECM内部化的新型调节剂及其在癌细胞入侵和转移中的作用.
- 在2D和3D癌症模型中研究ECM内细胞形成的功能意义.
主要方法:
- 开发了一种使用自动ECM涂层和pH敏感染料进行活细胞成像的高含量查试验.
- 利用遗传查来识别参与ECM内部化的关键蛋白质.
- 在实验室中评估了抑制已识别的蛋白质对癌细胞迁移和入侵的影响.
- 分析了患者瘤样本中的蛋白质表达.
主要成果:
- 确定了MAP3K1,MAPK11 (p38β) 和PPP2R1A作为内部化ECM结合的α2β1整合素的关键.
- 证明/质子交换器1 (NHE1) 可以调节ECM巨细胞,由p38.
- 识别的途径的破坏损害了癌细胞的迁移和入侵.
- 发现内化ECM被 lysosomally降解,支持细胞衍生基质上的细胞迁移.
- 在胰腺瘤中观察到α2β1整合素和MAP3K1表达的升高,与预后不佳相关.
- 在耐化疗乳腺瘤中发现关键途径组件的表达更高.
结论:
- α2β1整合素/p38信号轴是ECM内细胞分裂的新型调节器,驱动癌细胞入侵和进展.
- 对于侵袭性迁移来说,ECM巨细胞和随后的溶酶体降解至关重要.
- 开发的高含量查试验有效地识别了癌细胞入侵的新型调节者.
- 针对这种途径可能为侵袭性和耐化疗癌症提供新的治疗策略.
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