Targeting microtubule stabilization to reduce breast tumor metastasis

靶向微管稳定以减少乳腺肿瘤转移

• 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
• 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

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（由申请方提供）：已知细胞骨架改变会影响循环肿瘤细胞（CTC）的转移成功。然而，对肿瘤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显著知识空白。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与附着在细胞外基质上的细胞反应非常不同。具体而言，分离的肿瘤细胞产生独特的基于微管蛋白的微触角（McTN），其促进CTC重新附着到内皮细胞层。活体动物的成像表明，CTC通过与McTN匹配的细胞骨架机制重新附着在血管壁上。重要的是，由于McTNs由微管蛋白支持，因此常见的乳腺癌药物紫杉醇（Taxol）实际上增强了McTNs并加速了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的肿瘤细胞运动的癌症药物也增强了McTNs。这些结果强调了确定针对细胞分裂或附着的肿瘤细胞的运动性的癌症药物是否会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可以强烈增加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分子靶点可能增加转移风险是很重要的。近90%的人类实体瘤是由上皮细胞产生的癌，其大的尺寸和刚性通常导致其在狭窄的毛细血管中破碎。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，以发展重新附着到血管壁并逃避碎片的机制。PI实验室最近的工作已经确定，当微管通过遗传改变或化学处理稳定时，McTNs会增加。这项研究将测试这一假设，即微触角产生于特定的微管，可以有针对性地治疗，以减少乳腺肿瘤转移。这一假设的预测将在以下具体目标进行测试：1）定义 微管蛋白脱酪氨酸在McTN生成和转移中的作用。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中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，以及检查来自人类乳腺癌患者的CTC中McTN的发生率和功能，将识别新的治疗靶点并揭示当前癌症药物的潜在转移风险。