Role of N-Cadherin in Pancreatic Tumor Microenvironment

N-钙粘蛋白在胰腺肿瘤微环境中的作用

• 批准号: 8555506
• 负责人: KEITH R JOHNSON
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555506
• 关键词: Adenocarcinoma; Adenocarcinoma Cell; Benign; Biological; Cadherins; Cell Communication; Cells; Clinical Research; Collagen; Deposition; Disease; Distant; Environment; Epithelial Cells; Evolution; Genetic; Genetically Engineered Mouse; Goals; Growth; Human; In Vitro; Individual; Knock-out; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mesenchymal; Modeling; Molecular; N-Cadherin; Neoplasm Metastasis; Organ; Pancreas; Pancreatic Adenocarcinoma; Relative (related person); Role; Signal Transduction; Staging; Stromal Cells; Stromal Neoplasm; Testing; Tissues; Tumor Cell Invasion; Up-Regulation; Work; Xenograft Model; base; cancer invasiveness; cell behavior; cell motility; epithelial to mesenchymal transition; implantation; macrophage; mouse model; neoplastic cell; pancreatic neoplasm; stellate cell; tumor; tumor progression; tumorigenesis

Pancreafic adenocarcinomas are characterized by extensive deposition of collagen 1, which can have profound effects on cell behavior. We have shown that cells derived from pancreatic adenocarcinomas respond In vitro to exogenous collagen I by transforming from a non-motile epithelial cell to a highly motile and invasive mesenchymal cell. A hallmark of epithelial to mesenchymal transition is an increase in expression of the mesenchymal cadherin, N-cadherin. Keith's lab has been studying the role of N-cadherin in tumor progression for more than a decade, and we have convincingly demonstrated that upregulafion of N-cadherin expression converts epithelial cells from benign, non-mofile, non-invasive cells to highly mofile and invasive cells. From these studies, we hypothesized that N-cadherin promotes tumor cell invasion. Clinical studies from our lab and others have validated our hypothesis. Of particular significance to the current proposal is the fact that Ncadherin is expressed by more than 50% of invasive pancreatic tumors. Here, long-temn goal is to determine the molecular basis of N-cadherin-mediated invasiveness and metastasis in PC. Previous studies from our lab have demonstrated that N-cadherin knockdown in BxPC3 and Capani pancreatic adenocarcinoma cells can significantly decrease tumor progression and metastasis in orthotopic xenograft models. However, the role of individual components of the tumor microenvironment is not cleariy understood. Genetically engineered mouse models have been shown to faithfully mimic the genefic and biological evolufion of their human counterpart diseases. The hypothesis is that N-cadherin expression In multiple components of tumor microenvironment is critical for PC metastasis. We propose to test the hypothesis by generafing and ufilizing syngeneic tumor implantafion models with alterafions in N-cadherin expression in individual components of PC microenvironment. In addition to the critical role of N-cadherin expression in pancreafic adenocarcinoma cells in promoting cancer and metastasis, N-cadherin is also expressed and involved in the mofility of stellate cells as well as macrophages. Both, pancreafic stellate cells and macrophages have been shown to facilitate tumorigenesis and invasiveness of pancreatic adenocarcinoma cells. Thus, we further hypothesize that N-cadherin expression on pancreatic stellate cells and macrophages facilitates PC progression and invasion. Hence, we propose to test the relative contribufion of N-cadherin expression on stellate cells and macrophages toward PC progression and invasion by proposing the following specific aims: Aim 1: To determine the contribufion of N-cadherin-mediated adenocarcinoma cell-stromal cell interacfions in PC. Our working hypothesis of this aim is that N-cadherin mediates tumor-stromal interactions and N-cadherin expression on stromal cells facilitates their tumor recruitment. Aim 2: To determine the contribufion of N-cadherin-mediated adenocarcinoma cell-macrophage interacfions toward PC invasiveness. Our working hypothesis of this aim is that N-cadherin expression on macrophages facilitates their recruitment and acfivafion in the tumor cell compartments and facilitates PC progression.

胰腺癌的特点是胶原蛋白 1 广泛沉积，这可能对胰腺癌产生深远的影响。 对细胞行为的影响。我们已经证明源自胰腺腺癌的细胞在体外有反应 通过从非活动性上皮细胞转变为高度活动性和侵袭性的外源性胶原蛋白 I 间充质细胞。上皮细胞向间质细胞转化的一个标志是 间质钙粘蛋白，N-钙粘蛋白。 Keith 的实验室一直在研究 N-钙粘蛋白在肿瘤进展中的作用 十多年来，我们令人信服地证明了 N-钙粘蛋白表达的上调 将上皮细胞从良性、非运动性、非侵袭性细胞转化为高度运动性和侵袭性细胞。从这些研究中，我们假设 N-钙粘蛋白促进肿瘤细胞侵袭。我们实验室的临床研究和 其他人验证了我们的假设。对当前提案特别重要的是 Ncadherin 超过 50% 的侵袭性胰腺肿瘤表达。 这里的长期目标是确定 N-钙粘蛋白介导的侵袭和转移的分子基础 在电脑中。我们实验室之前的研究表明，BxPC3 和 Capani 中的 N-钙粘蛋白敲低 胰腺腺癌细胞可以显着降低原位肿瘤进展和转移 异种移植模型。然而，肿瘤微环境的各个组成部分的作用尚不清楚。 明白了。基因工程小鼠模型已被证明能够忠实地模仿基因和 人类对应疾病的生物进化。假设 N-钙粘蛋白表达 肿瘤微环境的多种成分对于 PC 转移至关重要。我们建议测试 通过生成和利用 N-钙粘蛋白改变的同基因肿瘤植入模型来提出假设 PC 微环境的各个组成部分中的表达。 胰腺癌细胞中 N-钙粘蛋白表达除了在促进癌症发生方面发挥关键作用外 N-钙粘蛋白也表达并参与星状细胞的运动以及转移 巨噬细胞。胰腺星状细胞和巨噬细胞均已被证明可促进肿瘤发生 和胰腺癌细胞的侵袭性。因此，我们进一步假设 N-钙粘蛋白 胰腺星状细胞和巨噬细胞上的表达促进 PC 进展和侵袭。 因此，我们建议测试 N-钙粘蛋白表达对星状细胞和巨噬细胞的相对贡献 通过提出以下具体目标来实现 PC 的进展和入侵： 目标 1：确定 N-钙粘蛋白介导的腺癌细胞-基质细胞相互作用在 个人电脑。我们对此目标的工作假设是 N-钙粘蛋白介导肿瘤-基质相互作用，并且 N-钙粘蛋白 基质细胞上的表达促进它们的肿瘤募集。 目标 2：确定 N-钙粘蛋白介导的腺癌细胞-巨噬细胞相互作用的贡献 走向 PC 入侵。我们对此目标的工作假设是巨噬细胞上的 N-钙粘蛋白表达 促进它们在肿瘤细胞区室中的募集和激活，并促进 PC 进展。