High-throughput intracellular microrheology: a new tool for cancer research

高通量细胞内微流变学：癌症研究的新工具

基本信息

批准号：
7586363
负责人：
Denis Wirtz
金额：
$ 24.12万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-08 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586363
关键词：
Actins Adhesions Advanced Malignant Neoplasm Aftercare Atomic Force Microscopy Ballistics Biological Assay Biomedical Engineering Biophysics Body Fluids Cancer Biology Carcinoma Cell Adhesion Cell Density Cell Line Cell membrane Cells Cellular biology Chemicals Chemistry Chemotherapy-Oncologic Procedure Clinical Collaborations Complement Complex Computers Cultured Tumor Cells Cytoplasm Cytoskeleton Detection Development Devices Diagnosis Diagnostic Discipline of obstetrics Disease Disease model Doctor of Philosophy Early Diagnosis Elasticity Engineering Epithelial Cells Equilibrium Etiology Evaluation Fluorescence Microscopy Growth Factor Gynecology Harvest Hospitals Immunofluorescence Immunologic Individual Injection of therapeutic agent Life Liquid substance Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Measurement Measures Mechanics Medicine Methods Microscope Molecular Morbidity - disease rate Nature Neoplasm Metastasis Normal Cell Operative Surgical Procedures Ovarian Ovarian Carcinoma Ovarian Serous Adenocarcinoma Pathology Patients Pharmaceutical Preparations Phenotype Positioning Attribute Property Recurrence Reproducibility Research Research Personnel Resolution Schools Serous Shapes Specimen Staging Stretching Students Surface Survival Rate Symptoms Testing Therapeutic Time Tumor Cell Invasion Tumor Debulking Viscosity Woman Work anticancer research base cancer cell cell injury cell motility cellular engineering chemotherapeutic agent chemotherapy density design high risk immortalized cell improved instrument medical schools migration mortality mouse model oncology particle pressure prevent prototype response tool wound

项目摘要

DESCRIPTION (provided by applicant): Cancer mortality and morbidity are critically related to tumor invasion and metastasis in which the molecular mechanisms are poorly understood. Until their etiology is better revealed, attempts to develop new cancer therapeutics would remain empirical. Cell motility, which drives cancer metastasis, involves dynamic and regulated re-arrangements of the cytoskeleton. Our work and that of several other groups have shown that cytoskeleton phenotypes are typically accompanied by drastic changes in the viscoelastic properties of the cytoskeleton, which in turn modulate the ability of the cytoskeleton to generate net pushing forces at the leading edge and allow the cell to change its shape. Changes in cell mechanical properties have long been predicted to correlate with metastatic potential. However, current cell-mechanics approaches suffer from serious drawbacks - including time of measurement, lack of multiplexing, ambiguity of measurements - which prevent a direct test of this important hypothesis. The objective of this study is to: develop a highly-optimized high-throughput ballistic injection nanorheology (htBIN) technological platform to measure the micromechanical properties in cancer cells rapidly (< 30 seconds per cell) and reliably, and to assess these biophysical properties as a function of cell migration and invasion by comparing ovarian cancer cells of low and high invasive nature to normal cells, all obtained from patients at the Johns Hopkins Hospital. The proposed instrument, which is based on multiple-particle microrheology, presents key advantages over current approaches to cell mechanics. Our device will serve as a new tool for cancer research to study cell mechanics in the context of cancer cell migration and adhesion, and may ultimately serve as a diagnostic tool for patients who are at high risk for ovarian cancer, complementing more conventional biomolecular markers of cancer in a clinical setting While our proposed approach to cell mechanics is a priori applicable to detect intracellular mechanical differences in any type of cancer cells, a primary focus of this project is ovarian cancer. Ovarian cancer was selected as the disease model in this study because it represents one of the most aggressive cancers in women.

描述（由申请人提供）：癌症死亡率和发病率与肿瘤侵袭和转移密切相关，但其分子机制尚不清楚。在更好地揭示其病因之前，开发新的癌症疗法的尝试仍将是凭经验进行的。驱动癌症转移的细胞运动涉及细胞骨架的动态和受调节的重新排列。我们和其他几个小组的工作表明，细胞骨架表型通常伴随着细胞骨架粘弹性特性的急剧变化，这反过来又调节细胞骨架在前缘产生净推力的能力，并允许细胞改变它的形状。长期以来，人们一直预测细胞机械特性的变化与转移潜力相关。然而，当前的细胞力学方法存在严重的缺陷——包括测量时间、缺乏多重性、测量的模糊性——这阻碍了对这一重要假设的直接检验。本研究的目的是：开发高度优化的高通量弹道注射纳米流变学 (htBIN) 技术平台，以快速（每个细胞 < 30 秒）可靠地测量癌细胞的微机械特性，并评估这些生物物理特性：通过将低侵袭性和高侵袭性的卵巢癌细胞与正常细胞进行比较来研究细胞迁移和侵袭的功能，所有这些细胞均从约翰·霍普金斯医院的患者获得。所提出的仪器基于多颗粒微流变学，与当前的细胞力学方法相比具有关键优势。我们的设备将作为癌症研究的新工具，研究癌细胞迁移和粘附背景下的细胞力学，并最终可能作为卵巢癌高危患者的诊断工具，补充更传统的卵巢癌生物分子标记物。临床环境中的癌症虽然我们提出的细胞力学方法首先适用于检测任何类型癌细胞的细胞内力学差异，但该项目的主要焦点是卵巢癌。卵巢癌被选为本研究的疾病模型，因为它是女性中最具侵袭性的癌症之一。