基于细胞力学特性研究辐射对神经胶质瘤转移潜能的影响及调控机制

Based on the aspect of cell mechanics, the project has been focused on the invasion and metastasis of cancer, which is the key scientific issue determined to the success or failure of radiation therapy. 1) On micro-scales, measure the influence of the surface morphology and mechanical properties induced by X- ray and heavy ion radiation in malignant glioma cells; 2) Identify the regulator effect between the alteration in biomechanical effects such as deformability and remodeling of cytoskeleton as well as mechanotransduction trigged by radiation, and metastatic potential of malignant glioma, and to find the mechano-biological coupling law between radiation-mediated mechanical response in tumor cells and the development of tumor cells; 3) Using the bioinformatics tools, screen the genes involved in cancer onset, progression and prognosis of malignant glioma, and obtain an important target－cytoplasmic scaffolding protein Moesin, and further verify radiation-mediated the expression , distribution and tissue localization of Moesin in vtro and in vivo; 4) Clarify the relationship between the mechanical cell signal or Moesin/CD44 pathway and metastatic potential in the glioma cells via silencing Moesin gene, and finally to find out the metastasis mechanism. This project provides a new idea for preventing and controlling recurrence and metastasis of malignant glioma.

基于细胞力学层面，聚焦于癌细胞侵袭和转移这一关乎癌症放射治疗成败的关键性科学问题：1）以微纳米尺度量化X-射线及重离子辐射对恶性神经胶质瘤细胞表面形貌与力学特性的影响；2）明确辐射引发的生物力学效应，包括细胞骨架变形、重构以及力学信号改变，对神经胶质瘤转移潜能的调控作用，寻找辐射介导的肿瘤细胞力学应答与肿瘤细胞发生发展之间的力学－生物学耦合规律；3）结合生物信息学手段，筛选与神经胶质瘤发病至预后密切相关的基因，挑选胞质内骨架蛋白Moesin为研究靶点，在离体胶质瘤细胞株和裸鼠胶质瘤模型中验证辐射诱导其表达、组织定位及蛋白分布；4）继而通过沉默Moesin基因，阐明辐射作用下肿瘤细胞机械力学信号或通路Moesin/CD44与恶性胶质瘤细胞转移潜能间的关联，从而揭示放射线作用于肿瘤侵袭和转移的内在力学机制。本项目的研究为防止和防治放射治疗神经胶质瘤中的复发、转移提供新的思路。

本项目聚焦细胞力学层面，研究了辐射对胶质瘤转移潜能的影响及调控机制，基本达到了预期目标。研究结果确定了重离子辐射作用下，胶质瘤细胞转移过程存在明显的机械力学应答，从细胞力学视角阐明了肿瘤的转移潜能。通过分析重离子束辐照诱导的基因差异性变化，发现了9个极其显著下调的基因，其中包括MSN信号、FAK信号以及Rho信号等重要通路，这些通路均可调控肿瘤细胞的运动，可能为临床治疗肿瘤复发转移筛选出有效的靶点。通过生物信息学分析发现MSN与胶质瘤患者的发生发展以及预后都有显著相关，更适合作为55岁以下胶质瘤患者的预测靶标并在临床样本中获得高度验证。通过对MSN干预，发现MSN作为机械力转导信号，调控了细胞骨架相关信号，改变了细胞的形变，抑制了胶质瘤细胞的迁移及浸润性生长。另外，本项目证实了MSN/CD44信号通路在重离子束介导的细胞运动中起到重要的调控作用。综上所述，研究结果为防止和防治神经胶质瘤的复发、转移提供了新思路。