Role of N-Cadherin in Pancreatic Tumor Microenvironment

胰腺癌的特点是广泛的胶原1沉积，它可以有深刻的 对细胞行为的影响。我们已经证明，来自胰腺癌的细胞在体外会产生反应 通过从不活动的上皮细胞转变为高度运动和侵袭性的外源性I型胶原 间充质细胞。上皮细胞向间充质细胞转化的一个特征是 间充质钙粘蛋白、N-钙粘蛋白。基思的实验室一直在研究N-钙粘附素在肿瘤进展中的作用 十多年来，我们已经令人信服地证明了N-钙粘素的表达上调 将上皮细胞从良性、非MOFILE、非侵袭性细胞转化为高度MOFILE和侵袭性细胞。从这些研究中，我们假设N-钙粘附素促进肿瘤细胞的侵袭。我们实验室的临床研究和 其他人证实了我们的假设。对目前的提案特别重要的是，Ncadherin 在超过50%的侵袭性胰腺肿瘤中都有表达。 在这里，Long-TEMN的目标是确定N-钙粘素介导的侵袭和转移的分子基础 在PC中。我们实验室以前的研究已经证明，N-钙粘素在BxPC3和Capani中被击倒 胰腺癌细胞可显著降低原位肿瘤的进展和转移 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忠实地模仿了基因和 人类相应疾病的生物学进化。假设N-钙粘附素在脑内的表达 肿瘤微环境的多种成分是PC转移的关键因素。我们建议测试一下 N-钙粘附素基因突变的同种异体肿瘤移植模型的建立和应用 在PC微环境的单个组件中表达。 除了N-钙粘素在胰腺癌细胞中的表达在促癌中的关键作用 和转移，N-钙粘附素也表达，并参与星状细胞的迁移以及 巨噬细胞。胰腺星状细胞和巨噬细胞都被证明促进肿瘤的发生。 和胰腺癌细胞的侵袭性。因此，我们进一步假设N-钙粘附素 胰腺星状细胞和巨噬细胞的表达促进了PC的进展和侵袭。 因此，我们建议测试N-钙粘素在星状细胞和巨噬细胞上的表达的相对贡献 通过提出以下具体目标来应对PC的进步和入侵： 目的1：探讨N-钙粘素介导腺癌细胞-基质细胞相互作用的作用机制。 PC机我们关于这一目标的工作假设是N-钙粘素介导肿瘤-间质相互作用和N-钙粘附素 基质细胞上的表达促进了它们的肿瘤侵袭。 目的2：确定N-钙粘附素介导腺癌细胞-巨噬细胞相互作用的作用 针对个人电脑的入侵。我们关于这一目的的工作假说是巨噬细胞上N-钙粘附素的表达 促进它们在肿瘤细胞间的募集和吞噬，并促进PC进展。

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.