Clinically-Relevant Regulatory Networks in the Lung Tumor Microenvironment

描述(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人死于肺癌。肺癌发生发展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知识来自于分离肿瘤细胞和微环境的单一成分之间的相互作用的研究，沿着单一的途径。我们将重建第一个肺腺癌的肿瘤微环境相互作用组(TMI)，它将识别人类恶性肿瘤细胞与其相关的浸润性免疫细胞、内皮细胞和成纤维细胞之间的全球细胞内和细胞间调控相互作用。TMI将来自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球基因表达分析，使用荧光激活细胞分类(特定目标1)。将使用新的计算方法重建TMI，以推断基因模块之间的调节(特定目标2)。从TMI，我们将确定候选的中介因子，如分泌的细胞因子，调节跨多个细胞亚群的过程。我们将通过利用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(特定目标2)。我们将在验证研究中使用细胞系和动物模型的组合来测试候选中介因素对肿瘤行为的影响(特定目标3)。通过重建的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上相关的分子靶点，这些靶点可以用于开发更有效的肺癌治疗方法。肺腺癌TMI还将作为评估感兴趣基因的作用的假说生成工具向科学研究界公开提供。 公共卫生相关性：我们采用系统生物学方法重建肺腺癌的调控网络，得出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，以及可能导致更有效治疗人类肺腺癌的现有分子靶向治疗药物的潜在组合。

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.