Biomechanics of Invading Breast Cancer Cells in 3D Matrices: Invadopodia Function

3D 矩阵中侵袭乳腺癌细胞的生物力学：侵袭伪足功能

• 批准号: 7682094
• 负责人: RYAN G MCALLISTER
• 金额: $ 14.79万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682094
• 关键词: Actin-Binding Protein; Actins; Address; Adherence; Adhesions; Behavior; Binding; Biological Assay; Biomechanics; Breast Cancer Cell; Caliber; Cell Adhesion; Cell Culture Techniques; Cell Surface Extensions; Cell surface; Cell-Matrix Junction; Cells; Cellular biology; Characteristics; Chemotactic Factors; Chemotaxis; Collagen; Complex; Comprehensive Cancer Center; Cytoskeleton; Development; Education; Environment; Experimental Designs; Extracellular Matrix; Extracellular Matrix Degradation; Face; Fiber; Filopodia; Focal Adhesions; Goals; Growth Factor; Ideal 1; Image; Image Analysis; Imaging Techniques; In Vitro; Intervention; Invaded; Knowledge; Label; Location; MMP14 gene; Malignant Neoplasms; Measurement; Measures; Mediating; Membrane; Mentors; Methods; Microscope; Microscopic; Microscopy; Microspheres; Modeling; Molecular; Morphogenesis; Neoplasm Metastasis; Optics; Pathway interactions; Penetration; Peptide Hydrolases; Phosphotransferases; Plasmids; Polymers; Process; Property; Proteolysis; Publishing; Quantum Dots; Relative (related person); Research; Research Design; Research Personnel; Resistance; Resolution; Role; Site; Small Interfering RNA; Speed; System; Techniques; Testing; Tissues; Training; Transfection; Tumor Cell Invasion; Variant; Wasps; Work; base; cancer cell; career; cell behavior; cell motility; design; experience; human EMS1 protein; improved; in vitro Assay; in vivo; indexing; insight; laser tweezer; migration; mutant; neoplastic cell; neuronal cell body; novel; polymerization; prevent; programs; protein aggregation; research study; response; rho; three-dimensional modeling; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): Invadopodia are thin cell membrane extensions detected in aggressive tumor cells and defined by their role in localized extracellular matrix degradation. The goal of the proposed research is to determine the involvement of invadopodia in breast cancer cell migration through 3D collagen networks and to determine which aspects of invadopodia function are critical for invasion. In 3D culture models, the candidate will 1) measure invadopodia-like membrane extensions, 2) determine the relationship between membrane extension and invadopodial complex formation, 3) develop a mechanistic model of the interconnections between cell-matrix adhesions, filopodia, invadopodia and to localized force exerted on the ECM and matrix degradation, and 4) determine the role of invadopodia in the response of chemotactic tumor cells to controlled chemoattractant gradients. As a result, the candidate will have built a unique set of tools to quantitatively model invasive cell behavior in 3D, and the research should produce new insights into the multi-faceted role of invadopodia in invasion. The proposed work provides the candidate with an ideal opportunity to achieve his career transition goal by 1) education in cancer cell biology, 2) training in in vitro cell and molecular techniques including cell culture, manipulation of plasmids and siRNA, transfection, and use of in vitro assays of cellular behavior focusing on cell motility and invasion, and 3) interaction with successful cancer cell biologists, including the mentor Dr. Susette Mueller, in the setting of the Lombardi Comprehensive Cancer Center. Relevance: Several cell surface features are thought to be required for migration and invasion: filopodia and lamellipodia formation, matrix-cell adhesions, and invadopodia. Yet the contribution of adhesion and matrix degradation at these localized sites to cellular invasion has not been studied adequately in a 3D cell culture environment. Some critical components of typical cancer cell behavior can likely only be reproduced in the context of a 3D environment. Experiments proposed here are important prerequisites to imaging tissue ex vivo and in vivo where the contribution of other complex effects of the microenvironment can be explored. An understanding of the significance of invadopodia for altering and moving through the extracellular matrix may identify new targets for intervention to prevent migration and metastasis, which would ultimately improve survival. Quantitative imaging, feature-tracking, and displacement-measurement in a 3D polymer matrix is challenging and requires researchers such as the candidate with experience in optical system design, image analysis, and quantitative experimental design and interpretation.

描述（由申请人提供）：浸润性瘤是在侵袭性肿瘤细胞中检测到的薄细胞膜延伸，并通过其在局部细胞外基质降解中的作用来定义。本研究的目的是通过三维胶原网络确定浸润性足与乳腺癌细胞迁移的关系，并确定浸润性足功能的哪些方面对浸润性足至关重要。在3D培养模型中，候选人将1)测量浸润样膜延伸，2)确定膜延伸与浸润样复合物形成之间的关系，3)建立细胞-基质粘附，丝状伪足，浸润样以及施加在ECM和基质降解上的局部力之间相互联系的机制模型，以及4)确定浸润样在趋化肿瘤细胞对控制的趋化梯度的反应中的作用。因此，候选人将建立一套独特的工具来定量模拟三维侵袭性细胞行为，并且该研究将对侵袭性细胞的多方面作用产生新的见解。