Multi-scale Molecular Imaging of the Degradome in Breast Tumors

乳腺肿瘤降解组的多尺度分子成像

基本信息

批准号：
8835062
负责人：
Kristine Glunde
金额：
$ 34.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835062
关键词：
Affect Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast cancer metastasis Cathepsins Cell Line Characteristics Collagen Type I Complex Cultured Tumor Cells Data Development Diagnostic Imaging Dyes Enzymes Extracellular Matrix Fiber Fluorescent Probes Functional Imaging Generations Genetic Engineering Growth Housing Human Image Imaging Techniques Invaded Lead Lesion Lysosomes Malignant Neoplasms Mammary Neoplasms Medical Metalloproteases Metastatic Lesion Microscopic Microscopy Monitor Neoplasm Metastasis Nodule Nonmetastatic Optics Organelles Peptide Hydrolases Play Primary Neoplasm Proteins Research Role Shapes Signal Transduction Solid Neoplasm Structure Surrogate Markers System Therapeutic Tumor Cell Invasion Tumor Tissue Urokinase Xenograft Model Xenograft procedure base cancer cell cancer therapy in vivo innovation insight malignant breast neoplasm molecular imaging non-invasive imaging novel optical fiber optical imaging second harmonic tumor tumor microenvironment tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Lysosomes are one of the most important cellular organelles in breast cancer invasion, metastasis, and extracellular matrix (ECM) remodeling, because they contain several degradative enzymes that can influence the integrity and structure of the ECM. The roles of lysosomes in the breast cancer degradome in vivo are virtually unexplored, due, in part, to a lack of noninvasive imaging capabilities available to visualize lysosomes. We recently developed and validated novel near-infrared fluorescent (NIRF) probes for noninvasive imaging of lysosomes in cell culture and tumors in vivo. Preliminary data obtained using these probes support the importance of lysosomes in breast cancer invasion and metastasis. We therefore intend to use these probes to understand and define the influence of lysosomes in cancer cells on invasion, metastasis, and ECM remodeling. Collagen type I (Col1) fibers are an important component of the ECM that can facilitate breast tumor formation, invasion, and metastasis. In this application, we will perform multi-scale molecular and functional imaging studies to characterize the Col1 fiber matrix in primary tumors and metastatic nodules to understand how Col1 fibers are shaped by the cancer degradome, and how this promotes invasion and metastasis. We will microscopically image Col1 fibers using innovative and clinically translatable optical second harmonic generation (SHG) microscopy, which detects an intrinsic optical signal from Col1 fibers. We will utilize the lysosome-specific NIRF probe IR-2 to image lysosomes in breast tumor models in vivo. We will optically image protease activities in vivo using MMPSense to detect matrix metalloprotease activities and ProSense to detect cathepsin activities. We will focus on understanding the role of lysosomes in breast tumor invasion in vivo in Aim 1, and in breast cancer metastasis in Aim 2 using multi-scale optical imaging approaches. In Aim 3, we will determine the influence of lysosomes and lysosomal enzymes on Col1 fiber structure and integrity in solid tumors and metastatic nodules in vivo. These three Aims will provide novel insights into the role of lysosomes and lysosomal enzymes within the overall degradome in breast cancer models. The proposed research will further our understanding of the role of lysosomes in cancer invasion, metastasis, and Col1 fiber remodeling, which may eventually lead to novel lysosome-based therapeutic strategies to treat cancer. Understanding the role of lysosomes and lysosomal enzymes in invasion, metastasis, and Col1 fiber remodeling may lead to the development of innovative diagnostic imaging techniques that noninvasively detect lysosomal probes as surrogate markers to assess invasiveness, metastatic potential, and Col1 fiber structure in these tumors.

描述（由申请人提供）：溶酶体是乳腺癌入侵，转移和细胞外基质（ECM）重塑中最重要的细胞细胞器之一，因为它们含有几种可能影响ECM完整性和结构的降解酶。溶酶体在体内乳腺癌降解组中的作用几乎没有探索，部分原因是缺乏可视化溶酶体的非侵入性成像能力。我们最近开发并验证了新型的近红外荧光（NIRF）探针，用于在体内对溶酶体的无创成像和体内肿瘤。使用这些探针获得的初步数据支持溶酶体在乳腺癌侵袭和转移中的重要性。因此，我们打算使用这些探针来理解和定义溶酶体对癌细胞对侵袭，转移和ECM重塑的影响。胶原型I型（COL1）纤维是ECM的重要组成部分，可促进乳腺肿瘤形成，侵袭和转移。在此应用中，我们将执行多尺度的分子和功能成像研究，以表征原发性肿瘤和转移结节中Col1纤维基质，以了解Col1纤维如何由癌症降解组塑造，以及这如何促进侵袭和转移。我们将使用创新和可翻译的光学第二次谐波生成（SHG）显微镜图像COL1纤维对COL1纤维进行图像，该光学可检测Col1纤维的固有光学信号。我们将利用溶酶体特异性的NIRF探针IR-2在体内对乳腺肿瘤模型中的溶酶体进行图像。我们将使用mmpsense在体内进行光学图像蛋白酶活动，以检测基质金属蛋白酶的活动和利益以检测组织蛋白酶的活动。我们将专注于使用多尺度光学成像方法在AIM 1中的乳腺肿瘤在AIM 1中的乳腺肿瘤侵袭中的作用，以及在AIM 2中的乳腺癌转移中的作用。在AIM 3中，我们将确定溶酶体和溶酶体对体内实体瘤和转移结节中Col1纤维结构的影响。这三个目标将提供有关乳腺癌模型总降解组中溶酶体和溶酶体酶作用的新见解。拟议的研究将进一步了解溶酶体在癌症侵袭，转移和COL1纤维重塑中的作用，这最终可能导致新的基于溶酶体的治疗癌症的治疗策略。了解溶酶体和溶酶体酶在侵袭，转移和COL1纤维重塑中的作用可能导致创新的诊断成像技术的发展，这些成像技术无创地检测溶酶体探针作为替代标志物，以评估这些象征性，转移性潜在和COL1纤维结构。