权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

(PQ7)Multi-scale Analysis of Tumor Microenvironment Heterogeneity

(PQ7)肿瘤微环境异质性多尺度分析

基本信息

批准号：
9378269
负责人：
DEAN W FELSHER
金额：
$ 72.94万
依托单位：
STANFORD UNIVERSITY
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：
2017-09-07 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9378269
关键词：
Acute Archives B-Lymphocytes Behavior Biological Markers Biological Models Blood Cell Communication Cells Clinical Clinical Research Collaborations Cytometry Data Dendritic Cells Dependency Detection Effector Cell Exhibits Flow Cytometry Frequencies Gastroenterologist Gene Expression Gene Expression Profiling Genes Grant Heterogeneity Human Human Resources Imaging technology Immune Immune response Immunotherapy In Situ Innate Immune System Institutional Review Boards Kinetics Laboratories Liver Liver neoplasms Location MYC gene Maintenance Malignant neoplasm of liver Measures Mediating Methods Modeling Molecular Multiplexed Ion Beam Imaging Neoplasm Metastasis Oncogenes Pathogenesis Pathologic Pathology Population Primary carcinoma of the liver cells Protocols documentation Recruitment Activity Regulation Research Personnel Role Specimen Stream Stromal Cells System T-Lymphocyte Subsets Technology Tetracyclines The Cancer Genome Atlas Time Tissue Microarray Training Transgenic Mice Transgenic Organisms Tumor Tissue Tumor stage Universities Work adaptive immune response base bioluminescence imaging cancer regression cell motility cell type cytokine data modeling ex vivo imaging imaging modality imaging program immune activation in vivo in vivo imaging intravital microscopy macrophage mathematical model member molecular imaging mouse model neoplastic cell novel oncogene addiction outcome forecast predictive modeling professor prospective reconstitution tool treatment response tumor tumor growth tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

ABSTRACT Tumorigenesis is associated with heterogeneous evolving changes of innate and adaptive immune effectors in the tumor microenvironment. Recording, identifying and quantifying these cellular and molecular changes could transform our understanding of tumorigenesis. We and others have shown that oncogenes, such as MYC co-opt and/or subvert these immune effectors, thereby evading immune detection and promoting a tumor microenvironment that fuels tumor growth; however, this appears to occur in a manner that necessarily and predictably leaves tumors highly vulnerable to acute oncogene inactivation, whereby immune effectors become activated, thereby resulting in dramatic tumor regression, a phenomenon called “oncogene addiction”. Hence, we hypothesize that the identification，quantification and localization of these different host immune effectors in the tumor microenvironment during tumorigenesis and tumor regression will identify cellular biomarkers that will predict therapeutic response to oncogene inactivation. Our approach will be to employ the Tet system regulated model of MYC-induced hepatocellular carcinoma (HCC) and MYC/Twist1-induced model of metastatic HCC. Then, to utilize: FACS/CyTOF, CODEX/MIBI, IVM/BLI, and Gene expression/CIBERSORT to identify cellular effectors and hallmark genes and metabolites. First, our transgenic mouse model of MYC- induced HCC has been widely utilized by us and many others. Employing the Tet System, our model exhibit precise reversible and titrable control of the gene expression of the MYC oncogene. Tumor formation occurs slowly over time, oncogene-dependency results in tumor regression that is highly dependent on the immune response. Further, recently we generated a not published mouse model dramatically illustrating that MYC- induced liver tumors rapidly metastasize through the blood stream when combined with transgenic Twist1 expression. Twist1 has previously been associated with metastasis. We have obtained preliminary results that show metastasis is associated with and appears to require recruitment of macrophages. Finally, we have found that we can use human TCGA data available to identify potential cellular effectors associated with the pathogenesis of human HCC. Thus, all stages of tumorigenesis appear to be dependent on the stromal and immune response (initial, progressed, metastatic, regressed) and represent a unique tool to assess tumor- microenvironment heterogeneity. We have three aims: first, to dissect the mechanism by which the adaptive and innate immune system facilitates HCC progression, metastasis, and regression; second, to determine the kinetics and localizations of the above identified cell populations using in vivo (IVM and BLI) imaging technologies with special emphasis on cell-cell interactions and, third, to assess the ability of these findings to make predictions regarding the clinical behavior and prognosis of human HCC.

摘要