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Imaging mechanisms of metastatic tumor formation in situ

原位转移性肿瘤形成的成像机制

基本信息

批准号：
10491345
负责人：
Gaudenz Danuser
金额：
$ 160.93万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10491345
关键词：
3-Dimensional Adaptor Signaling Protein Address Adopted Affect Algorithms Architecture Automobile Driving Biological Biological Assay Biological Models Blood Vessels Cancer Biology Cancer Etiology Carcinoma in Situ Cells Cellular Morphology Cellular biology Cessation of life Chemicals Clinical Treatment Communities Computer Vision Systems Core Facility Data Development Disease Distant Educational workshop Embryo Environment Environmental Risk Factor Event Ewings sarcoma Extracellular Matrix Goals Heterogeneity Human Image Imaging Device Immunofluorescence Immunologic In Situ Individual Informatics Institution Intelligence Intrinsic factor Invaded Investigation Label Light Malignant - descriptor Malignant Bone Neoplasm Malignant Neoplasms Membrane Membrane Proteins Metabolic Metabolism Methods Microscope Microscopy Molecular Molecular Analysis Molecular Probes Morphology Mus NCI Center for Cancer Research Neoplasm Metastasis Oncogenic Optics Organ Organism Pattern Periodicity Physiological Pilot Projects Play Primary Neoplasm Process Property Research Research Personnel Resolution Role Sampling Series Side Signal Transduction Site Solid Neoplasm Specimen Speed Subgroup System Technology Testing Thick Tissue imaging Tissues Training Tropism Variant WNT Signaling Pathway Work Xenograft procedure Zebrafish cancer cell caveolin 1 cell behavior childhood sarcoma cloud based dimensional analysis experimental study fluorescence imaging functional adaptation high dimensionality high resolution imaging high throughput screening imaging approach imaging platform imaging probe imaging program intravital imaging lipid metabolism live cell imaging lymphatic vessel melanoma molecular imaging multimodality multiplexed imaging novel outreach programs quantitative imaging response technology development tumor xenograft

项目摘要

Project Summary In response to the RFA for a Cellular Cancer Biology Imaging Program we propose a program focused on imaging and molecularly probing the cell biological events that drive the formation of new metastatic tumors. Specifically, we will address two questions: 1) How does the intersection of shifts in cell-intrinsic and cell- extrinsic signals associated with shifts in expression of the membrane adaptor protein Caveolin-1 affect the metastatic propensity of pediatric sarcoma (Research Testbed Unit 1)? 2) What are the effects of cell-intrinsic and cell-extrinsic variation in lipid metabolism on melanoma metastasis patterns (Research Testbed Unit 2)? Answers to both questions depend on technology to capture the molecular, metabolic, and morphological states of individual metastatic cells as they colonize the distant site: In the Technology Development Unit-1 we will develop a multi-modal, multi-scale live imaging platform to investigate the effects of intersecting microenvironmental variation across an organism and cell intrinsic heterogeneity on metastatic spreading. The platform will leverage the exquisite optical and physiological properties of the zebrafish embryos to ‘watch’ at once how cells form human tumor xenografts spread to multiple distant sites where they form metastatic tumors. The microscope will allow seamless switching between a high-throughput screening mode observing the metastatic patterns in tens to hundreds of embryos in one experiment and a high-resolution imaging mode with fully isotropic resolution of 300 nm in XYZ that allows detailed analysis of the molecular, metabolic, morphologic, and proliferation/survival states of individual cells within an emerging metastatic niche. In the Technology Development Unit-2 we will develop a multi-scale imaging platform to investigate by hyper-spectral analysis the molecular, metabolic, morphological, and functional states of metastatic cells across entire mouse organs. The platform will leverage advances in tissue clearing, fully automated high-speed and high-resolution light-sheet fluorescence imaging, and computer vision, to integrate a mesoscopic imaging mode for fast acquisition of volumes of up to 20 x 20 x 20 mm at a ~5-10 micron isotropic resolution with a nanoscopic imaging mode providing 300 nm XYZ-resolution throughout a 300 micron field of view anywhere in the organ. Biological features can thus be rapidly identified and immediately interrogated with high subcellular resolution. We will then develop physically and chemically accelerated 60-plex cyclic immunofluorescence assays to comprehensively characterize the molecular, metabolic and architectural states of colonizing cells and their surroundings in the metastatic niche in thick (~200 microns) tissue sections. To accurately describe metastatic heterogeneity, the entire system, including sample handling, labeling, and imaging, will be fully automated and operated in a high-throughput fashion. Our goal with this system is to enable comprehensive profiling of heterogeneous cell metastatic cell behavior in 100’s of intact tissue specimens. Together, these platforms will generate versatile imaging tools for a new era of in situ cancer cell biology.

项目总结