mTORC1调解双相机械反应以协调依附性细胞生长和阿诺基的抗性
Chunlei Zhang1,2, Yuan Wang1,2, Zifeng Zhen1,2
1Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
|December 2, 2023
概括
癌细胞将其新陈代谢适应机械线索. 这项研究揭示了一个整合素-GSK3β-FTO-mTOR通路,可以控制硬表面的生长,并在矩阵脱离时抵抗细胞死亡,从而提供潜在的癌症标.
科学领域:
- 细胞生物学 细胞生物学
- 癌症生物学 癌症生物学
- 代谢调节 代谢调节 代谢调节
背景情况:
- 细胞动态感知并响应生物力学微环境线索,需要代谢适应才能生存和繁殖.
- 细胞外基质 (ECM) 刚性与癌症的攻击性有关,而基质脱离 (anoikis 抵抗) 下的生存与预后不佳相关.
- 了解瘤细胞的非线性机械反应对于确定新的治疗点至关重要.
研究的目的:
- 阐明瘤细胞集成来自微环境的机械信号的分子机制.
- 为了确定一个信号轴,它调节了对基质刚性和脱落的反应中的代谢适应.
- 探索在癌症中准这种机械传感途径的治疗潜力.
主要方法:
- 研究了整合素-GSK3β-FTO-mTOR信号轴在调解细胞对基质刚性的反应中的作用.
- 利用生物化学测试和分子生物学技术来分析mtORC1激活和mRNA N6-甲基氨酸 (m6A) 修饰.
- 检查了ECM脱落对癌细胞自和anoikis耐药性的影响,包括人类乳腺管道癌 in situ (DCIS) 和小鼠炎模型.
主要成果:
- 基质硬化激活了整合素-GSK3β-FTO-mTOR通路,导致mTOR水平升高,并通过m6A修饰增强了合成代谢.
- 在ECM脱离时抑制这一轴促进了自,从而产生了对anoikis (脱离诱导的细胞死亡) 的抵抗力.
- 这种双相机械调节的新陈代谢在DCIS和恶性炎模型中都被观察到,突出显示了它对癌症进展和转移的相关性.
结论:
- 整合素-GSK3β-FTO-mTOR轴作为机械线索的关键整合器,决定癌细胞的代谢适应和生存策略.
- 这一途径促进瘤在刚性基板上的生长,并在转移过程中赋予瘤抵抗力.
- 针对这种机械调节轴是一个有希望的治疗策略,用于打击癌症的攻击性和转移.
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