Microfluidic platform for tumor cell invasion

肿瘤细胞侵袭的微流控平台

• 批准号: 9383728
• 负责人: Mingming Wu
• 金额: $ 37.99万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383728
• 关键词: Adhesions; Animals; Architecture; Automobile Driving; Biochemical; Biological; Biological Assay; Biophysics; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Cell Adhesion Molecules; Cells; Cessation of life; Clinical; Coculture Techniques; Collagen; Collagen Fiber; Communication; Complex; Cues; Disseminated Malignant Neoplasm; Distant; Endothelial Cells; Engineering; Environment; Evaluation; Event; Extracellular Matrix; Gel; Generations; Goals; Image; Immune; In Vitro; Individual; Knowledge; Lead; Location; Lymphatic vessel; Malignant Neoplasms; Mammary Neoplasms; Mechanics; Mediating; Methods; Microfluidics; Modeling; Neoplasm Metastasis; Physiological; Plasticizers; Play; Population; Positioning Attribute; Primary Neoplasm; Process; Property; Regulation; Research; Role; Secondary to; Signal Transduction; Site; Stream; Stromal Cells; Time; Tissues; Traction; Tube; Tumor Cell Invasion; Tumor Cell Migration; Venous; Work; base; biological systems; biophysical analysis; biophysical properties; cancer cell; cancer imaging; capillary; cell motility; cell type; cellular imaging; cytokine; fluid flow; imaging potential; in vitro Model; innovation; interstitial; intravital imaging; lymph flow; macrophage; migration; neoplastic cell; network architecture; novel diagnostics; population based; real time model; screening; tool; trafficking; treatment strategy; tumor; tumor microenvironment; Adhesions; Animals; Architecture; Automobile Driving; Biochemical; Biological; Biological Assay; Biophysics; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Cell Adhesion Molecules; Cells; Cessation of life; Clinical; Coculture Techniques; Collagen; Collagen Fiber; Communication; Complex; Cues; Disseminated Malignant Neoplasm; Distant; Endothelial Cells; Engineering; Environment; Evaluation; Event; Extracellular Matrix; Gel; Generations; Goals; Image; Immune; In Vitro; Individual; Knowledge; Lead; Location; Lymphatic vessel; Malignant Neoplasms; Mammary Neoplasms; Mechanics; Mediating; Methods; Microfluidics; Modeling; Neoplasm Metastasis; Physiological; Plasticizers; Play; Population; Positioning Attribute; Primary Neoplasm; Process; Property; Regulation; Research; Role; Secondary to; Signal Transduction; Site; Stream; Stromal Cells; Time; Tissues; Traction; Tube; Tumor Cell Invasion; Tumor Cell Migration; Venous; Work; base; biological systems; biophysical analysis; biophysical properties; cancer cell; cancer imaging; capillary; cell motility; cell type; cellular imaging; cytokine; fluid flow; imaging potential; in vitro Model; innovation; interstitial; intravital imaging; lymph flow; macrophage; migration; neoplastic cell; network architecture; novel diagnostics; population based; real time model; screening; tool; trafficking; treatment strategy; tumor; tumor microenvironment

Project Summary Cancer metastasis accounts for over 90% of all cancer deaths. A limiting step in cancer metastatic cascade is for tumor cells to migrate towards, interact with and squeeze through the blood vessel wall before disseminating to secondary tumor sites via the blood circulation. Biophysical forces, including interstitial and intramural flows, have shown to play critical roles in regulating adhesion molecules, spatial cytokine distributions and tissue architecture; all of which contribute to tumor cell invasion within 3D biomatrix. Despite the clinical importance, roles of biophysical forces in tumor cell transendothelial migration (TEM) are poorly understood. This is in part due to the lack of in vitro tools that are able to follow tumor cell transmigration events in real time, and with well controlled biological flows. Current animal cell invasion assay, the Boyden Chamber, is limited because it is difficult to recreate complex tumor microenvironment. In addition, the results are population based at two time end points. Intravital imaging has advanced significantly our understanding about the interplays between tumor microenvironment and TEM in a physiologically realistic setting. However, it is difficult to dissect the contribution of individual environmental cues to TEM processes. The goals of the proposed research are to develop a physiologically realistic microfluidic model with well controlled tumor microenvironment for studies of tumor cell TEM processes; and to identify tumor microenvironment that promotes TEM. To achieve these goals, we will develop an organotypic microfluidic model for real time imaging of tumor cell TEM events under well controlled micro-environment. We will use the location of spheroid and cell streaming event to guide TEM imaging sites. Using the microfluidic model, we will explore the relations between single tumor cell properties and TEM activities under well controlled interstitial and intramural flows. Previous work from the PI’s lab and others have indicated that interstitial flows critically regulate tumor cell migration within 3D biomatrix. Here, we hypothesize that tumor cells’ TEM capabilities are closed correlated with cells’ microenvironment including fluid flows. The proposed project is innovative because it represents the first generation of organotypic microfluidic platform that includes both interstitial and intramural flows, moving the current microfluidic tumor model towards a physiologically realistic direction. Lessons learned here will eventually lead to knowledge important for developing novel diagnostic or/and treatment strategies for cancer. This platform can be readily extended for use in other biological systems where TEMs are important including immune cell trafficking.

项目摘要 癌症转移占所有癌症死亡的90％以上。癌症转移性级联的限制步骤是 肿瘤细胞朝向，与血管壁相互作用和挤压之前 通过血液循环传播到二次肿瘤部位。生物物理力，包括间质和 壁内流，已证明在稳定粘合分子，空间细胞因子中起关键作用 分布和组织结构；所有这些都导致3D Biomatrix内的肿瘤细胞侵袭。尽管 临床重要性，生物物理力在肿瘤细胞跨内皮迁移（TEM）中的作用很差 理解。这部分是由于缺乏能够跟随肿瘤细胞传播的体外工具 实时发生事件，并具有良好的生物流动。目前的动物细胞入侵测定法，博伊登 腔室之所以受到限制，是因为很难重现复杂的肿瘤微环境。另外，结果 是基于两个时间端的人口。弹刻成像已经大大提高了我们的理解 关于在物理逼真的环境中肿瘤微环境与TEM之间的相互作用。然而， 很难剖析单个环境线索对TEY过程的贡献。目标的目标 拟议的研究是开发具有良好控制肿瘤的物理逼真的微流体模型 用于研究肿瘤细胞温度过程的微环境；并确定肿瘤微环境 促进TEM。为了实现这些目标，我们将为实时开发一个有机微流体模型 在良好控制的微环境下，肿瘤细胞TEM事件的成像。我们将使用 球体和细胞流媒体事件可引导TEM成像位点。使用微流体模型，我们将 探索单个肿瘤细胞特性与受良好控制下的TEM活动之间的关系 室内和壁内流动。 PI实验室的先前工作和其他工作表明 流动严格调节3D Biomatrix内的肿瘤细胞迁移。在这里，我们假设肿瘤细胞 TEM功能与细胞的微环境（包括流体流动）相关。提议 项目具有创新性，因为它代表了第一代有机微流体平台 包括间隙和壁内流，将电流微流体肿瘤模型移动到A 生理上现实的方向。在这里汲取的教训最终将导致对 开发新颖的诊断或/和癌症治疗策略。这个平台可以很容易扩展 用于TEMS重要的其他生物系统，包括免疫细胞运输。