细胞张力感受器talin调节非小细胞肺癌转移的力学机制研究

细胞内力学活动是肿瘤侵袭转移必不可缺的因素，因缺乏胞内力学检测手段而其调控机制少见报道。通过构建以荧光共振能量转移为原理的生物探针，将活细胞微观力学变化转换为光学信号，我们前期研究发现：张力感受器talin头部能增强整合素依赖的胞内渗透压力，而杆状尾部能传递微丝向内牵拉力，两者协同诱导非小细胞肺癌侵袭转移的发生。本项目拟进一步研究：与talin头部结合的蛋白通过调节整合素/PLCγ/Chronophin/cofilin信号通路，诱导骨架解聚及蛋白纳米颗粒生成，上调胞内向外渗透压力。talin杆状尾部ABS或VBS结构域与微丝或黏着斑蛋白结合，促进微丝张力向质膜传递，继而增强渗透压力的定向作用及肿瘤细胞侵袭转移。上述两种方向依赖的力学活动能协同诱导“单位张力或压强”增强，促进板状或丝状伪足增多及肺癌侵袭转移。本项目研究可以从力学角度为抑制非小细胞肺癌侵袭转移，提供新的药物研发靶点。

Intracellular mechanical activity is an indispensable factor for tumor invasion and metastasis, and its regulatory mechanism is rarely reported due to the lack of intracellular mechanical detection methods. By constructing a biological probe based on the principle of fluorescence resonance energy transfer to convert the micromechanical changes of living cells into optical signals, our previous study found that the head of the tension sensor talin can enhance the integrin-dependent osmotic pressure in live cells, while its rod tail can transmit inward pulling force ofmicrofilament, and both result synergistically in invasion and metastasis of non-small cell lung cancer. This project intends to use molecular and cell biology techniques to further analyze: the protein bound to the head of Talin regulates the integrin/PLCγ/Chronophin/cofilin signaling pathway to induce cytoskeleton depolymerization and protein nanoparticle production, and up-regulate intracellular osmotic pressure. The ABS or VBS domain of the rod tail of talin binds to microfilaments or focal adhesion proteins to promote the transmission of microfilament force to the plasma membrane, thereby enhancing the directional effect of osmotic pressure and then inducing tumor invasion and metastasis. The two direction-dependent mechanical activities synergistically contribute to the enhancement of "unit tension or pressure", which promotes the increase of plate or filopodia and the invasion and metastasis of lung cancer. The research of this project can provide a new drug development target for inhibiting the invasion and metastasis of non-small cell lung cancer.