Control of Tumor Cell – Bone Metastasis By Regulation of F-Actin Dynamics

通过调节 F-肌动蛋白动力学控制肿瘤细胞 â 骨转移

• 批准号: 401164232
• 负责人: Professor Dr. Rolf Jessberger
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/401164232?language=en
• 关键词: Control; Tumor; Cell; Bone; Metastasis

This project aims at revealing a key pathway, which is currently too little understood: the contribution of F-actin dynamics and proteins that govern this to metastasis, particularly bone metastasis. Indeed, highly active F-actin dynamics has been designated a hallmark for aggressive, metastasizing cancer cells. We hypothesized that SWAP-70 as a unique type of F-actin binding and bundling protein is a prime candidate to be involved in metastasis and, as we now showed, indeed supports tumor cell metastasis. Our aim is to analyze and understand this role on as many relevant levels as possible: from metastasis in animals to cellular, molecular and biophysical aspects. The first funding period has yielded very interesting insights into both, the in vivo role of SWAP-70 in metastasis and into the molecular and cellular functions of SWAP-70 related to metastasis. It became clear that metastasis by SWAP-70 deficient tumor cells is much reduced and that SWAP-70 contributes a number of F-actin related cellular and molecular properties to tumor cells important for metastasis. We will now perform investigations in further developed animal models and deepened in vitro studies of mechanistic aspects of SWAP-70’s contribution to F-actin dynamics related to metastasis. Our two overall aims are (1) Determine the role of SWAP-70 in tumor cell bone metastasis in vivo, and (2) Define SWAP-70 dependent, F-actin related features of bone metastatic tumor cells in vitro.To reveal structure-function features of SWAP-70 related to metastasis we will use specific mutants of the protein in vivo and in cell culture assays, i.e. in complementation experiments. Metastasis to the bone, also to the lung, CTC formation and properties, and tumor cell exosome properties and effects will be analyzed in animal models. In vitro we will molecularly characterize SWAP-70 dependent features of exosomes and their biological effects, will perform a selection of migration, adhesion, spheroid formation and colony formation assays, will determine F-actin dynamics and biophysical cell features such as cell deformability and stiffness depending on SWAP-70. This combination of in vivo and in vitro experiments will allow us to define the SWAP-70/F-actin dependent mechanism in metastasis and in mid term enable the development of new therapeutic avenues.

该项目旨在揭示一个目前知之甚少的关键途径：f -肌动蛋白动力学和控制其转移的蛋白质的贡献，特别是骨转移。事实上，高度活跃的f -肌动蛋白动力学已被指定为侵袭性转移癌细胞的标志。我们假设SWAP-70作为一种独特类型的f -肌动蛋白结合和捆绑蛋白是参与转移的主要候选者，并且正如我们现在所显示的，确实支持肿瘤细胞转移。我们的目标是在尽可能多的相关层面上分析和理解这种作用：从动物转移到细胞、分子和生物物理方面。第一个资助期对SWAP-70在体内转移中的作用以及SWAP-70与转移相关的分子和细胞功能都产生了非常有趣的见解。很明显，SWAP-70缺陷肿瘤细胞的转移大大减少，SWAP-70为肿瘤细胞提供了许多与f -肌动蛋白相关的细胞和分子特性，这些特性对转移很重要。我们现在将在进一步开发的动物模型中进行研究，并在体外深入研究SWAP-70对与转移相关的f -肌动蛋白动力学的作用机制。我们的两个总体目标是：(1)确定SWAP-70在体内肿瘤细胞骨转移中的作用；(2)确定体外骨转移肿瘤细胞依赖SWAP-70的F-actin相关特征。为了揭示SWAP-70与转移相关的结构-功能特征，我们将在体内和细胞培养试验中使用该蛋白的特定突变体，即在互补实验中。转移到骨，也转移到肺，CTC的形成和性质，以及肿瘤细胞外泌体的性质和作用将在动物模型中进行分析。在体外，我们将分子表征SWAP-70依赖性外泌体的特征及其生物学效应，将进行迁移，粘附，球体形成和集落形成的选择分析，将确定f -肌动蛋白动力学和生物物理细胞特征，如细胞变形性和刚度取决于SWAP-70。这种体内和体外实验的结合将使我们能够确定SWAP-70/ f -肌动蛋白在转移中的依赖机制，并在中期开发新的治疗途径。