(7) Novel imaging devices for measurement and control of tumor microenvironments

(7)用于肿瘤微环境测量和控制的新型成像装置

• 批准号: 9900579
• 负责人: JOHN S CONDEELIS
• 金额: $ 57.96万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900579
• 关键词: Address; Affect; Anatomy; Animals; Antibodies; Area; Biological; Biological Process; Biological Products; Biological Sciences; Biophysics; Blocking Antibodies; Breast; Breast cancer metastasis; Cancer Biology; Cancer Model; Catalogs; Cell Density; Cell physiology; Cell surface; Cells; Cellular biology; Cessation of life; Chemical Agents; Chemicals; Correlative Study; Diagnosis; Disease model; Dose; Endothelial Cells; Evolution; Expression Profiling; Extracellular Matrix; Fluorescent Antibody Technique; Gene Expression Profiling; Hypoxia; Image; Imaging Device; Immune; In Vitro; Individual; Investigation; Label; Light; Location; Lung; Malignant Neoplasms; Mammary Neoplasms; Measurement; Microfluidics; Microscopy; Modeling; Molecular; Multimodal Imaging; Mus; Neoplasm Metastasis; Optics; Pathologist; Phenotype; Physics; Primary Lesion; Primary Neoplasm; Process; Reaction Time; Recurrence; Research Personnel; Resolution; Risk; Role; Secondary Lesion; Signal Pathway; Signal Transduction; Site; Stains; Stromal Cells; Structure; Supporting Cell; System; Techniques; Technology; Testing; Therapeutic; Time; Tissue Stains; Tissue imaging; Tissues; Uncertainty; Woman; Work; behavioral phenotyping; cell behavior; cell motility; cell type; chemotherapy; density; design; driver mutation; experience; experimental study; fluorescence lifetime imaging; human tissue; in vivo; in vivo imaging; interest; intravital imaging; laser capture microdissection; macrophage; malignant breast neoplasm; materials science; mimetics; mouse model; movie; neoplastic cell; novel; novel imaging technology; novel strategies; physical science; prevent; prognostic value; programs; response; sample fixation; targeted agent; tool; tumor; tumor heterogeneity; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT Understanding the identity, location and function of cells in the tumor microenvironment is essential to understanding how they dominate tumor phenotype and contribute to dissemination and metastasis. An example of this is the tri-partite structure TMEM (for Tumor MicroEnvironment of Metastasis) consisting of the juxtaposition of a macrophage, an endothelial cell and a tumor cell which function together to act as the doorway for metastatic dissemination. We have created novel imaging technologies consisting of 1)implantable windows with embedded microfluidics that allow serial high-resolution, single-cell microscopy of the primary and metastatic sites over days to weeks, and 2)multi-modal image alignment technologies to register fixed, stained, tissue sections to each other or to the acquired intravital imaging movies. Light activated valves embedded in the microfluidic system will be used to deliver microenvironment-altering chemical (e.g. hypoxia mimetics, chemotherapy) and biological (e.g. function blocking antibodies) agents and label unmarked tissues with fluorescent antibodies, all while imaging the tissue response in real time. Intravital imaging will be used to image the tissue and provide single-cell resolution images that cover the entire tissue over time spans ranging from seconds, to days, and even weeks. Finally, motile cells will be captured, either by chemo-attraction to microfluidic chambers, or laser capture microdissection after fixation, for further expression profiling. Application of these technologies to the study of primary and secondary lesions an unprecedented ability to probe the identity, location, quantity and function of the cells composing the heterogeneous microenvironment. Further, testing, in vivo, the targeting agents affecting the distribution, function and dynamics of the cells forming TMEM, as well as and the cells with which they interact, will enable the rapid determination of those agents with best therapeutic potential. This work will determine how 1) hypoxia, ECM density, immune cell density and chemotherapy initiate and define tumor heterogeneity in the primary and secondary sites; 2) chemotherapy and known blockers of TMEM assembly and function affect the dynamics of intravasation and dissemination in the primary and secondary sites; and 3) the relationship between cellular behavior and phenotype with cellular identity and location. The techniques utilized in this project are generally applicable and will allow molecular identification, localization and quantification of tumor heterogeneity in many cancers and disease models.

项目总结/摘要 了解肿瘤微环境中细胞的身份、位置和功能对于 了解它们如何支配肿瘤表型并促进扩散和转移。一个 这方面的实例是由以下组成的三分结构TMEM（用于转移的肿瘤微环境）： 巨噬细胞、内皮细胞和肿瘤细胞的并置，它们一起起作用， 转移性扩散的通道我们创造了新的成像技术， 1)具有嵌入式微流体的可植入窗口，允许连续高分辨率单细胞显微镜检查 在数天至数周内对原发部位和转移部位进行定位，以及2）多模式图像对准技术， 将固定的、染色的组织切片彼此配准或与所采集的活体成像影片配准。光 嵌入微流体系统的激活阀将用于提供微环境改变 化学（例如低氧模拟物、化学疗法）和生物（例如功能阻断抗体）试剂 用荧光抗体标记未标记的组织，同时对组织反应进行真实的成像。 活体成像将用于对组织进行成像，并提供覆盖组织的单细胞分辨率图像。 整个组织随时间的变化范围从数秒到数天甚至数周。最后，运动细胞将 捕获，通过化学吸引到微流体室，或激光捕获显微切割后， 固定，用于进一步的表达谱分析。将这些技术应用于研究初级和 继发性病变是一种前所未有的能力，可以探测细胞的身份，位置，数量和功能 构成异构微环境。此外，在体内测试靶向剂， 形成TMEM的细胞的分布、功能和动力学，以及与它们一起形成TMEM的细胞。 相互作用，将能够快速确定那些具有最佳治疗潜力的药物。这项工作将 确定1）缺氧、ECM密度、免疫细胞密度和化疗如何启动和定义肿瘤 主要和次要部位的异质性; 2）化疗和已知的TMEM阻滞剂 组装和功能影响原发性和继发性肿瘤的内渗和播散动力学 3）细胞行为和表型与细胞身份和位置之间的关系。 本项目中使用的技术是普遍适用的，并将允许分子鉴定， 在许多癌症和疾病模型中定位和定量肿瘤异质性。