用细胞物理方法在三维肿瘤微球体系中研究癌症的形成和侵袭机理及抗癌药物的作用

Cancer is now the most important threat to the health of human beings, of which the dangers are not only the mad growth, but also the invasion and metastasis to other sites, resulting in high fatality rate. Although we have obtained a large number of biological and medical knowledge through the long-term research, and have invented anti-cancer drugs, the death rate of cancer is still not reduced. The key lies in the lack of understanding of cancer. Recently, physicists began to study cancer and analyzed the behavior of cancer cells from the physical point of view. They have found many laws of cancer that are universal, quantitative, and accurate, which greatly deepens our understanding of cancer. In this project, based on our previous cellular physics research, we will use 3D tumorsphere in vitro to study the physical characteristics of the cells in both stages of tumor formation and invasion. The physical characteristics includes intracellular diffusion, active transport, cell hardness, volume, surface area, migration speed, etc. By comparing benign and malignant tumorsphere, we can not only explore the key physical features of cancer, but also understand the mechanisms of cancer occurrence and metastasis. We will also study the effect of anticancer drugs on the physical characteristics of cells in tumor formation and invasion, to analyze the mechanism of drug action and measure the anticancer effect of drugs. This study will help us to explore the nature of cancer, and search for more effective cancer diagnosis and drug treatment options.

癌症即恶性肿瘤，当今人类生命健康的最主要威胁，其危害不仅在于癌症的疯狂生长，而且能侵袭转移到其他部位，造成高致死率。尽管人类通过长期研究掌握了大量生物和医学知识，发明了抗癌药物，癌症死亡率并没能降低，其关键在于缺乏对癌症的理解。最近，物理学者开始研究癌症，在物理角度分析癌细胞的行为，发现很多具有普适性、定量性和精确性的规律，极大加深了人们对癌症的认识。本项目将在我们细胞物理研究的基础上，通过体外构建三维肿瘤细胞微球，研究肿瘤形成和侵袭两阶段的细胞物理特征，包括细胞内扩散、主动运输、细胞的硬度、体积、表面积、迁移速度等，并通过比较良性和恶性肿瘤微球，不仅可寻找刻画癌症的关键物理特征，还可帮助我们理解癌症发生和转移的机理。我们还将研究抗癌药物对肿瘤形成和侵袭中细胞物理特征的影响，以分析药物的作用机理，衡量药物的抗癌效果。本项究将有助于探究癌症的本质，寻求更为有效的癌症诊断和药物治疗方案。

肿瘤作为当今威胁人类生命健康的最常见疾病之一，其危害性不仅是肿瘤细胞的生长和扩张，更严重的是肿瘤的侵袭转移。尽管生物学领域已经对肿瘤开展了长期的研究，但是对于肿瘤的物理特征、动力学及调控规律仍不清楚。本项目在生物大分子、细胞、以及细胞外微环境不同层次，开展了肿瘤的生物物理研究，项目达成了预定目标，取得了一系列重要进展，共发表了15篇论文，包括PNAS，Nature Communications, JACS等。我们通过建立三维肿瘤细胞微球实验体系，发展细胞内三维单分子荧光跟踪实验技术，构建了较为完整的实验技术平台和可靠的实验方案。在此基础上，我们研究了肿瘤细胞的多种物理特征及调控机制，包括发现了肿瘤细胞在上皮间质转化过程中的整合素扩散增强和极性分布，研究了肿瘤细胞内的三维输运特性，测定了肿瘤细胞外侧基底膜的物理特征及其对肿瘤侵袭的约束作用等。我们还研究在单分子水平上定量解析了染色质核小体结构组装和受到新型抗癌药CBL0137调控的分子机制。这些研究不仅有助于探究肿瘤的生长和侵袭机制，为临床医学研究提供基础理论支撑，而且恶行肿瘤的物理特征也可作为恶化检查标志，为肿瘤的早期发现与治疗提供新的线索。

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