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Early tumorigenesis in vivo imaging, scRNA-seq to functional assays

早期肿瘤发生体内成像、scRNA-seq 到功能测定

基本信息

批准号：
10540327
负责人：
SCOTT E FRASER
金额：
$ 18.9万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-13 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540327
关键词：
Ablation Address Adopted Adoption Adult Automobile Driving Basement membrane Behavior Benign Biological Assay Carcinoma Cell Differentiation process Cell Fraction Cell Proliferation Cell Separation Cell physiology Cells Complex Data Dermis Development Distal Drug Screening Epidermis Epithelial Cells Event Excision Exhibits Foundations Gene Expression Gene Expression Profile Genes Goals Growth Harvest Heterogeneity Image Imaging Device Individual Inequality Invaded Label Lasers Link Maintenance Malignant - descriptor Malignant Neoplasms Molecular Motivation Natural History Neoplasm Metastasis Oncogenes Organ Outcome Pathway interactions Phase Phenotype Play Population Positioning Attribute Process Proliferating Recording of previous events Reporter Resolution Role Route Skin Skin Tissue System Testing Time Tissues Transgenic Organisms Tumor Cell Invasion Tumor Cell Migration Tumor stage Visualization Zebrafish cancer imaging cell behavior cell type design experimental study imaging study in vivo in vivo Model in vivo imaging insight mature animal migration neoplastic cell non-invasive imaging novel marker prevent single-cell RNA sequencing spatiotemporal therapeutic target transcriptome transcriptomics tumor tumor growth tumor heterogeneity tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Tumor heterogeneity, in cell behavior, cell microenvironment and gene expression, has become a hallmark of tumor progression, and provides an important challenge in understanding cancer. For example, the adoption of an invasive phenotype by some tumor cells is a key step as carcinomas advance from the benign tumor state. Migration of tumor cells from the epithelial layers of the epidermis to the dermis provides tumor cell access to the vasculature, offering a direct path for distal metastasis. Understanding how and why some cells are capable of invading surrounding tissues is key to understanding tumor invasion, but current in vivo models of invasion do not readily allow specific invasive cells to be recovered and studied to elucidate drivers of tumor invasion and progression. Our goal is to create a new pipeline for following tumorigenesis, permitting direct studies of tumor cell diversification and invasion. This experimental pipeline is designed to offer capabilities to: (i) track tumorigenesis longitudinally over time from the first origins of a tumor to key events such as invasion; (ii) label and selectively purify tumor cell subsets identified in these time-course studies; (iii) characterize individual tumor cells in isolated populations in unbiased way. This approach would allow identification of the cellular events and developmental trajectories that accompany tumor growth and invasiveness. Molecular correlates characterized in the key sub-fractions of the tumors can be directly related to the event history of the cell sub-fractions, and the importance of these cellular and molecular events can be tested through perturbation, ablation and function blocking experiments. Such a functional and longitudinal experimental pipeline is key to creating more targeted and informative drug screening systems. We have developed a set of transgenic zebrafish lines and imaging tools that allow repeated, non-invasive visualization of endogenous tumor development in adult animals. This permits tumors to be tracked from their origins, over long periods, after oncogene expression in skin epithelial cells. Our preliminary results show that heterogeneity is present from the earliest stages of tumor formation, as only a small fraction of cells induced to express oncogenes go on to form invasive tumors; such results provide the motivation for and the foundation for our analyses of the emergence and elaboration of tumor heterogeneities. Here, we propose to employ imaging and labeling of selected cell populations, in combination with single-cell RNA-sequencing analyses, to study the cell behaviors and differentiation routes key to invasive tumor development. We will establish an experimental pipeline by investigating: the cell-types specific to invasive tumors (Aim 1); the key differentiation pathways leading to an invasive phenotype (Aim 2); and leveraging these insights by functional assays (Aim 3). This pipeline will offer new insights into invasive tumor development, supporting larger studies and the design of anti-tumor therapeutics targeting key cell subsets.

项目总结/文摘