细胞群体迁移启动机理的理论建模和实验研究

Collective cell migration is a kind of cluster migration behavior with specific migration direction, which is coordinated by multi-cells through intercellular and cell-basal connections. It is common in the physiological and pathological processes such as embryo development, wound healing and cancer metastasis. At present, there is still a lack of unified understanding on the initiating mechanism of collective cell migration, especially on how tumor cells carry out collective migration, which directly hinders the understanding of the mechanisms of tumor metastasis. It is worth mentioning that in the treatment of tumor-related diseases, in order to inhibit the spread of tumor cells, the commonly used means, such as interventional therapy, radiotherapy, chemotherapy, etc., all focus on the elimination of tumor cells. Recent studies have shown that the mechanochemical properties of tumor cells and their microenvironment are closely coupled, and the treatment that only kills off tumor cells without changing their abnormal microenvironment often has great side effects and poor prognosis over patients. Based on this, the project will be carried out by means of theoretical modeling and experimental research, focusing on the critical scientific problems in the process of cancer metastasis, such as the behavior of collective cell migration, the role of extracellular matrix mechanochemical properties, and the interactions between cells and between cells and extracellular matrix. The project will clarify the initiating mechanisms and corresponding regulatory mechanism of collective cell migration, and provide a new idea for exploring clinically the inhibition of cancer metastasis.

细胞群体迁移是多细胞通过细胞间，细胞-基底间连接协调完成的一种具有特定迁移方向的集群式迁移行为，普遍存在于胚胎发育、伤口愈合及癌症转移等生理病理过程中。目前关于细胞群体迁移的启动机制，尤其是关于肿瘤细胞如何进行群体迁移尚缺乏统一的认识，这直接阻碍了对肿瘤转移机理的理解。值得一提的是，在治疗与肿瘤相关的疾病过程中，为抑制肿瘤细胞扩散，常用的手段如介入治疗、放疗、化疗等，均聚焦于肿瘤细胞的清除。近年来的研究表明，肿瘤细胞与其微环境的力学化学性质耦合得非常紧密，仅仅清除肿瘤细胞而不调节其异常的微环境的治疗往往副作用很大，病人预后较差。基于此，本项目将通过理论建模和实验研究的方式，针对癌症转移过程中细胞群体迁移行为、细胞外基质的力学化学性质、细胞间及细胞-基底间的协作机理等关键科学问题展开研究，以期阐明细胞群体迁移的启动机理及其调控机制，为临床上探索抑制肿瘤转移提供一种新的思路。

本项目关注细胞群体迁移过程中形成的指状结构，该结构在多种生物过程中具有重要作用，如血管生长和癌症转移。然而，指状结构形成的机理及其后续演化仍未完全理解。本项目通过达西定律和线性稳定性分析，揭示了细胞单层指状失稳的临界波长和与牵引力、表面张力以及抗弯刚度之间的关系。研究发现，指状失稳源于迁移前缘的微扰动，且表面张力和抗弯刚度有助于平衡微扰。理论分析与实验观测相吻合。此外，建立了细胞单层迁移前缘的变分模型，将其视为具有弹性梁性质的弹性梁，通过变分理论推导了弹性梁波长和振幅之间的关系，并发现实验结果与模型吻合。同时，提出了指状结构速度场和应力场的液晶极化模型，并通过理论预测了速度和振幅之间的关系，结果与实验相符。最后，还研究了应力场和速度场随不同参数变化的情况。这些研究成果对于深入理解细胞群体迁移的机制具有重要意义。

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