(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

基本信息

批准号：
10202499
负责人：
JOHN S CONDEELIS
金额：
$ 58.15万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202499
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

项目摘要

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.

项目概要/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主导肿瘤表型并促进扩散和转移。一个例如，三部分结构 TMEM（肿瘤转移微环境）由以下部分组成：巨噬细胞、内皮细胞和肿瘤细胞并置，共同发挥作用转移性传播的门户。我们创造了新颖的成像技术，包括 1）具有嵌入式微流体的可植入窗口，可实现连续高分辨率、单细胞显微镜检查数天至数周内的原发性和转移性部位的检测，以及 2) 多模态图像对准技术将固定、染色的组织切片相互配准或与采集的活体成像电影配准。光嵌入微流体系统中的激活阀将用于提供微环境改变化学剂（例如缺氧模拟剂、化疗）和生物剂（例如功能阻断抗体）并用荧光抗体标记未标记的组织，同时实时成像组织反应。活体成像将用于对组织进行成像并提供覆盖整个组织的单细胞分辨率图像。整个组织的时间跨度从几秒到几天，甚至几周不等。最后，运动细胞将通过微流体室的化学吸引或激光捕获显微切割来捕获固定，用于进一步的表达谱分析。将这些技术应用于初级和中级研究继发性病变具有前所未有的探测细胞身份、位置、数量和功能的能力组成异质微环境。此外，在体内测试影响的靶向剂形成 TMEM 的细胞以及它们所包含的细胞的分布、功能和动力学相互作用，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引发和定义肿瘤主要和次要地点的异质性； 2) 化疗和已知的 TMEM 阻滞剂组装和功能影响初级和次级的内渗和传播动态网站； 3）细胞行为和表型与细胞身份和位置之间的关系。该项目中使用的技术具有普遍适用性，并且可以进行分子鉴定，许多癌症和疾病模型中肿瘤异质性的定位和量化。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Chemotherapy-induced metastasis: mechanisms and translational opportunities.

DOI：
10.1007/s10585-017-9870-x
发表时间：
2018-04
期刊：
Clinical & experimental metastasis
影响因子：
4
作者：
Karagiannis GS;Condeelis JS;Oktay MH
通讯作者：
Oktay MH

SUN-MKL1 Crosstalk Regulates Nuclear Deformation and Fast Motility of Breast Carcinoma Cells in Fibrillar ECM Microenvironment.

DOI：
10.3390/cells10061549
发表时间：
2021-06-19
期刊：
Cells
影响因子：
6
作者：
Sharma VP;Williams J;Leung E;Sanders J;Eddy R;Castracane J;Oktay MH;Entenberg D;Condeelis JS
通讯作者：
Condeelis JS

A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation.