Clinically-Relevant Regulatory Networks in the Lung Tumor Microenvironment

肺肿瘤微环境中的临床相关监管网络

基本信息

批准号：
8231607
负责人：
MICHAEL CLARKE
金额：
$ 60.2万
依托单位：
STANFORD 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：
2011-09-23 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231607
关键词：
Accounting Adenocarcinoma Cell Adopted Animal Model Behavior Biological Cancer Etiology Cell Culture Techniques Cell Line Cells Cessation of life Clinical Communities Complex Copy Number Polymorphism Data Data Set Development Disease Drug Delivery Systems Endothelial Cells Fibroblasts Flow Cytometry Fluorescence-Activated Cell Sorting Gene Expression Generations Genes Goals Human Immune Knowledge Lead Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Stromal Cell Malignant neoplasm of lung Mediating Mediator of activation protein Methods Molecular Molecular Profiling Molecular Target Operative Surgical Procedures Outcome Pathway interactions Patients Population Process Public Domains Regulation Regulator Genes Research Role Specimen Stromal Cells Stromal Neoplasm Systems Biology Testing Training Treatment outcome Tumor Cell Invasion Tumor-Derived United States Validation Work base cancer cell cell type clinically relevant cytokine effective therapy functional genomics improved interest mouse model new therapeutic target novel research study therapeutic target tool tumor validation studies

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States, accounting for approximately 160,000 deaths in 2009. The molecular mechanisms implicated in lung cancer development and progressions are not well understood. Recent evidence points to a complex interaction between the malignant cells and their microenvironment. However, much of our knowledge of the role of the tumor microenvironment comes from studies isolating the interactions between the malignant cells and a single component of the microenvironment, along a single pathway. We will reconstruct the first Tumor Microenvironment Interactome (TMI) of lung adenocarcinoma, which will identify global intra- and inter-cellular regulatory interactions between human malignant cells and their associated infiltrating immune cells, endothelial cells and fibroblasts. The TMI will be derived from global gene expression analysis of specific tumor microenvironment cell populations directly obtained from human lung cancer specimens using fluorescence-activated cell sorting (Specific Aim 1). The TMI will be reconstructed using novel computational approaches for inferring regulation among modules of genes (Specific Aim 2). From the TMI, we will identify candidate mediating factors, such as secreted cytokines, that regulate processes across the multiple cell subpopulations. We will specifically focus on the factors most associated with survival outcomes, by leveraging public domain expression data with long term survival outcomes (Specific Aim 2). We will use a combination of cell lines and animal models in the validation studies to test the effect of the candidate mediating factors on tumor behavior (Specific Aim 3). Through the reconstructed TMI, we will create a more global understanding of the lung tumor microenvironment. Our ultimate goal is to identify biologically and clinically relevant molecular targets that could be used to develop more effective therapies for lung cancer. The lung adenocarcinoma TMI will also be made publically available to the scientific research community as a hypothesis generation tool for evaluating the role of genes of interest. PUBLIC HEALTH RELEVANCE: We adopt a systems-biology approach to reconstruct a regulatory network of lung adenocarcinoma, deriving intra- and inter-cellular interactions. Our work promises to reveal novel therapeutic targets, as well as potential combinations of existing molecularly-targeted therapeutics that could lead to more effective treatment of human lung adenocarcinoma.

描述（由申请人提供）：肺癌是美国癌症死亡的主要原因，2009 年约有 160,000 人因肺癌死亡。肺癌发生和进展所涉及的分子机制尚不清楚。最近的证据表明恶性细胞与其微环境之间存在复杂的相互作用。然而，我们对肿瘤微环境作用的大部分了解来自于沿着单一途径分离恶性细胞与微环境的单一成分之间的相互作用的研究。我们将重建第一个肺腺癌肿瘤微环境相互作用组（TMI），它将识别人类恶性细胞与其相关的浸润免疫细胞、内皮细胞和成纤维细胞之间的整体细胞内和细胞间调节相互作用。 TMI 将源自使用荧光激活细胞分选直接从人类肺癌标本中获得的特定肿瘤微环境细胞群的全局基因表达分析（具体目标 1）。 TMI 将使用新颖的计算方法来重建，以推断基因模块之间的调节（具体目标 2）。从 TMI 中，我们将确定候选介导因子，例如调节多个细胞亚群过程的分泌细胞因子。我们将通过利用具有长期生存结果的公共领域表达数据，特别关注与生存结果最相关的因素（具体目标 2）。我们将在验证研究中结合使用细胞系和动物模型来测试候选介导因子对肿瘤行为的影响（具体目标 3）。通过重建TMI，我们将对肺肿瘤微环境有更全面的了解。我们的最终目标是确定生物学和临床相关的分子靶点，可用于开发更有效的肺癌疗法。肺腺癌 TMI 也将作为评估感兴趣基因作用的假设生成工具向科学研究界公开。公共健康相关性：我们采用系统生物学方法来重建肺腺癌的调控网络，推导细胞内和细胞间的相互作用。我们的工作有望揭示新的治疗靶点，以及现有分子靶向疗法的潜在组合，从而更有效地治疗人类肺腺癌。