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In vivo imaging of tumor heterogeneity generation from endogenous single cells

内源性单细胞肿瘤异质性产生的体内成像

基本信息

批准号：
9178032
负责人：
SCOTT E FRASER
金额：
$ 21.53万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178032
关键词：
Address Adult Animals Automobile Driving Back Benign Biological Blood Vessels Categories Cell Differentiation process Cell Lineage Cell Proliferation Cell division Cells Characteristics Detection Development Developmental Biology Distal Drug resistance Epidermis Epithelium Flow Cytometry Freezing Gene Expression Generations Genes Heterogeneity Image Image Analysis Individual Invaded Investigation Label Lead Life Link Lymph Malignant - descriptor Malignant Neoplasms Methods Modeling Molecular Neoplasm Metastasis Oncogenes Pathway Analysis Pathway interactions Phenotype Population Process Proliferating Property Proteins Reporter Role Sequence Analysis Skin Stem cells System Therapeutic Tissues Transgenic Organisms Tumor Angiogenesis Tumor Cell Invasion Tumor-Associated Process Tumor-Derived Work Zebrafish anti-cancer therapeutic base benign state cancer imaging cancer stem cell cell behavior cell type early onset in vivo in vivo imaging interest mature animal molecular marker neoplastic cell next generation sequencing non-invasive imaging novel prevent research study self-renewal tool transcriptome tumor tumor growth tumor heterogeneity tumor microenvironment tumorigenesis

项目摘要

PROJECT SUMMARY The formation of a malignant tumor from a benign tumor has been strongly linked to the existence of heterogeneous cellular features within the tumor. Thus, elucidating the mechanisms underlying generation of tumor cell heterogeneity will be an important milestone to understand malignant tumor formation. We believe two applications of our work could be 1) earlier, more quantitative detection of malignancy based on molecular markers and 2) therapeutics that can freeze tumor development before metastasis or even revert back to a benign state. Our approach is to answer the following two questions: 1. What is the impact of the tumor-initiating cell‘s identity on generating tumor cell heterogeneity? In experiments to date, the inability to avoid contamination of different cell origins, including tissue stem cells and non-stem cells into the resultant tumor mass has prevented identification of the precise molecular mechanisms. We address the contamination problem by establishing an experimental system that enables precise tracing of tumor cell lineage derived from single cells. Our method is the non-invasive, in vivo imaging of endogenous, single cell-derived tumor development in adult transparent zebrafish. This experimental system allows us to visualize individual tumor cells, and, more importantly, also selectively label and isolate the cells of interest for detailed cell characterization. Using this system, we have already imaged the tumors arising from single cells in the skin epithelium. Importantly, we have found some major differences in tumor cell proliferation between tumorous cell clusters and in tumor cell differentiation that lead to acquisition of invasive features. Our results identifying a subset of tumor cells displaying invasive features is nicely representing the generation of tumor cell heterogeneity within a tumor. We will perform long-term clonal analysis of tumor development and transcriptome analysis of isolated individual tumors to determine their cellular identity. Retrospective imaging analysis will be used to study the effect of a tumor’s microenvironment on generating tumor cell heterogeneity. 2. How is heterogeneity within a tumor established? Identification of the cell types of tumor-initiating cells will be followed by the investigation of the mechanisms driving a single tumor-initiating cell to become heterogeneous during multiple rounds of cell divisions. Our ability to distinctively label and isolate invasive tumor cells from non-invasive tumor cells enables us to investigate the gene expression modulations responsible for a subset of tumor cells acquiring invasive features during tumor development. We will further perform functional experiments in vivo to define the roles of specific molecular pathways in tumor invasion.

项目总结