Investigating the Tumor Microenvironment in Tumor Progression and Metastasisin Lu

癌症的进展由发育中的癌细胞的内在变化决定，也由重要的 癌细胞与肿瘤微环境的其他成分之间的相互作用。肺癌是 是美国和世界范围内癌症死亡的主要原因。尽管最近在肺癌方面取得了进展 尽管如此，晚期疾病患者的长期存活率仍然非常低。使用经过深思熟虑的 小鼠侵袭性和转移性非小细胞肺癌(NSCLC)模型及人肺 癌细胞株和人类癌症标本，我们将表征和功能测试 细胞外基质(ECM)和肿瘤间质中的一种特定细胞类型对肿瘤生物学的影响， 包括肿瘤进展。项目2有三个具体目标。目标1侧重于功能特性 Tenascin C(TNC)，一种ECM成分，参与了多种肿瘤的进展 设置，包括在此型号的NSCCL中。我们将使用基于细胞的方法和整体动物方法来 研究TNC功能的操纵对癌症进展的影响。在目标2中，我们将使用ECM 用于鉴定参与癌细胞黏附并可能影响细胞外基质成分的微阵列 侵袭性和转移性行为。筛选研究，这将在两者的细胞中进行 老鼠和人类的起源，接下来将进行功能分析。AIM 3利用先进的遗传方法 在已建立的晚期非小细胞肺癌中操纵与癌症相关的成纤维细胞的工程，以便 研究这种细胞群体中粗大和更细微的变化对癌细胞的影响 生物学。为此目的开发的方法也可以应用于其他与癌症相关的研究 肿瘤微环境中的细胞群。这个项目有可能发现肿瘤间质 调节癌症进展的关键方面的相互作用。这些交互作用的功能验证 可能导致治疗人类非小细胞肺癌和/或阻止其进展的新的治疗策略。 项目2通过与以下各项的多次交互很好地集成到此TMAN应用程序的更大结构中 其他每个项目和调查组。

Cancer progression is determined by intrinsic changes in the developing cancer cells as well as by important interactions between the cancer cells and other components of the tumor microenvironment. Lung cancer is the leading cause of cancer death in the United States and woridwide. Despite recent progress in lung cancer treatment, long-term survival rates for individuals with late-stage disease remain very poor. Using a wellstudied mouse model of invasive and metastatic non-small cell lung cancer (NSCLC) as well as human lung cancer cell lines and human cancer specimens, we will characterize and functionally test components of the extracellular matrix (ECM) and a specific cell type within tumor stroma for their effects on tumor biology, including tumor progression. Project 2 has three Specific Aims. Aim 1 is focused on functional characterization of Tenascin C (TNC), an ECM component that has been implicated in tumor progression in a variety of settings, including in this model of NSCCL. We will use both cell-based and whole animal approaches to examine the effects of manipulation of TNC function on cancer progression. In Aim 2, we will use an ECM microarray to identify additional ECM components that participate in cancer cell adhesion and may affect aspects of invasive and metastatic behavior. Screening studies, which will be carried out with cells of both mouse and human origin, will be followed by functional analysis. Aim 3 utilizes advanced methods in genetic engineering to manipulate cancer-associated fibroblasts within established, late-stage NSCLC, in order to investigate the consequences of gross and more subtle alternations within this cell population for cancer cell biology. The methods developed for this purpose can also be applied to the study of other cancer-associated cell populations within the tumor microenvironment. This project has the potential to uncover tumor-stromal interactions that mediate critical aspects of cancer progression. The functional validation of these interactions could lead to new therapeutic strategies for treating NSCLC in humans and/or to prevent its progression. Project 2 is well integrated into the larger structure of this TMEN application through multiple interactions with each of the other projects and investigator groups.