Targeting microtubule stabilization to reduce breast tumor metastasis

靶向微管稳定以减少乳腺肿瘤转移

基本信息

批准号：
8688930
负责人：
STUART S MARTIN
金额：
$ 30.9万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-06 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688930
关键词：
Acetylation Actins Affect Animals Antineoplastic Agents Binding Binding Proteins Bioluminescence Blood Vessels Blood capillaries Cancer Patient Carboxypeptidase Carcinoma Cell Adhesion Cell division Cells Chemicals Confocal Microscopy Cultured Cells Cultured Tumor Cells Cytoskeleton Distant Electron Microscopy Endothelial Cells Endothelium Epithelial Cells Extracellular Matrix FDA approved Future Generations Goals Human Image Immunomagnetic Separation Incidence Invaded Knowledge Lead Left Life Lung Malignant Epithelial Cell Mammary Neoplasms Mammary gland Measures Microtubule Stabilization Microtubules Modification Molecular Molecular Structure Molecular Target Mus Mutation Neoadjuvant Therapy Neoplasm Circulating Cells Neoplasm Metastasis Operative Surgical Procedures Paclitaxel Patients Pharmaceutical Preparations Psychological reinforcement Publishing Regulation Research Retinal blind spot Risk Role Site Solid Neoplasm Speed Structure Surface Testing Tissues Transplantation Treatment Efficacy Tubulin Tumor Cell Line Vimentin Work anticancer research base cancer imaging capillary cell growth cell motility chemotherapy drug development efficacy testing epithelial to mesenchymal transition extracellular improved malignant breast neoplasm mouse model neoplastic cell new therapeutic target pressure response restraint success tau Proteins tau expression therapeutic development therapeutic target tumor tyrosyltubulin ligase whole animal imaging

项目摘要

DESCRIPTION (provided by applicant): Cytoskeletal alterations are known to influence the metastatic success of circulating tumor cells (CTCs). However, studies of the tumor cell cytoskeleton are almost exclusively focused on cells attached to surfaces or extracellular matrix leaving a significant knowledge gap relevant to metastasis. Recent work from the PI's research group has demonstrated that the cytoskeleton of detached and circulating tumor cells responds very differently from cells attached to extracellular matrix. Specifically, detached tumor cells produce unique tubulinbased microtentacles (McTNs) that promote the reattachment of CTCs to endothelial cell layers. Imaging in live animals has demonstrated that CTCs reattach to blood vessel walls via a cytoskeletal mechanism that matches McTNs. Importantly, since McTNs are supported by tubulin, the common breast cancer drug, Paclitaxel (Taxol), actually strengthens McTNs and speeds tumor cell reattachment. Developing cancer drugs aimed at inhibiting attached tumor cell motility by targeting the actin cytoskeleton also enhance McTNs. These results emphasize the importance of determining whether cancer drugs aimed at cell division or the motility of attached tumor cells could have inadvertent effects that would actually increase metastatic risk. Since both surgery and neoadjuvant chemotherapy can strongly increase the levels of CTCs, it is important to understand which molecular targets will reduce the metastatic efficiency of CTCs and which may increase metastatic risk. Nearly 90% of human solid tumors arise as carcinomas from epithelial cells, whose large size and rigidity often lead to their fragmentation in narrow capillaries. This restraint on metastatic efficiency could impose a selective pressure for circulating carcinoma cells to develop mechanisms to reattach to blood vessel walls and escape fragmentation. Recent work in the PI's lab has identified that McTNs are increased when microtubules are stabilized via either genetic alterations or chemical treatments. This study will test the hypothesis that microtentacles arise from specific reinforcements of microtubules that can be targeted therapeutically to reduce breast tumor metastasis. Predictions of this hypothesis will be tested in the following specific aims: 1) Define the role of tubulin detyrosination during McTN generation and metastasis. 2) Target expression of the microtubule-binding protein, Tau, to reduce McTNs. 3) Use orthotopic mouse model and patient-derived CTCs to gauge paclitaxel effects on McTNs. The long-term goals of this project are to define the molecular mechanisms that govern microtubule stabilization in circulating tumor cells. Extending our understanding of McTN structure and molecular regulation as well as examining McTN incidence and function in CTCs derived from human breast cancer patients will both identify novel therapeutic targets and reveal potential metastatic risks of current cance drugs.

描述（由申请人提供）：已知细胞骨架的改变会影响循环肿瘤细胞（CTC）的转移成功。然而，肿瘤细胞细胞骨架的研究几乎完全集中在附着于表面或细胞外基质的细胞上，留下了与转移相关的重大知识空白。 PI 研究小组最近的工作表明，分离和循环肿瘤细胞的细胞骨架的反应与附着在细胞外基质上的细胞的反应非常不同。具体来说，分离的肿瘤细胞产生独特的基于微管蛋白的微触手 (McTN)，促进 CTC 重新附着到内皮细胞层。活体动物成像表明，CTC 通过与 McTN 相匹配的细胞骨架机制重新附着在血管壁上。重要的是，由于 McTN 得到微管蛋白的支持，常见的乳腺癌药物紫杉醇（紫杉醇）实际上可以增强 McTN 并加速肿瘤细胞的重新附着。开发旨在通过靶向肌动蛋白细胞骨架来抑制附着肿瘤细胞运动的癌症药物也能增强 McTN。这些结果强调了确定针对细胞分裂或附着肿瘤细胞运动的癌症药物是否可能产生实际上会增加转移风险的无意影响的重要性。由于手术和新辅助化疗都会强烈增加 CTC 的水平，因此了解哪些分子靶点会降低 CTC 的转移效率以及哪些可能会增加转移风险非常重要。近 90% 的人类实体瘤是由上皮细胞产生的癌，其较大的尺寸和刚性常常导致其在狭窄的毛细血管中碎裂。这种对转移效率的限制可能会对循环癌细胞施加选择性压力，以形成重新附着到血管壁并逃避破碎的机制。 PI 实验室最近的工作发现，当通过基因改变或化学处理稳定微管时，McTN 会增加。这项研究将检验这样的假设：微触手是由微管的特定强化产生的，可以通过靶向治疗来减少乳腺肿瘤转移。该假设的预测将在以下具体目标中进行测试：1）定义微管蛋白去酪氨酸化在 McTN 生成和转移过程中的作用。 2) 微管结合蛋白 Tau 的靶向表达，以减少 McTN。 3) 使用原位小鼠模型和患者来源的 CTC 来评估紫杉醇对 McTN 的影响。该项目的长期目标是确定控制循环肿瘤细胞微管稳定的分子机制。扩展我们对 McTN 结构和分子调控的理解，并检查来自人类乳腺癌患者的 CTC 中 McTN 的发生率和功能，将确定新的治疗靶点并揭示当前癌症药物的潜在转移风险。