Annexin A2 as a mediator of pancreatic cancer metastases

膜联蛋白 A2 作为胰腺癌转移的介质

基本信息

批准号：
8712421
负责人：
Lei Zheng
金额：
$ 32.61万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-02 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8712421
关键词：
ANXA2 gene Adenocarcinoma Cell Adopted Annexins Antigens Binding Cell Line Cell surface Cells Clinical Coculture Techniques Communication Complex Cytosol Development Disease Drug resistance Effectiveness Epithelial Epithelium Erinaceidae Event Fibroblasts Gene Chips Genes Goals Hepatocyte Growth Factor Human In Vitro Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Intervention Investigation Knock-in Mouse Knock-out Knockout Mice Lesion Link Lymphatic Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Mesenchymal Mesenchymal Stem Cells Mus Mutation Neoplasm Metastasis Outcome Pancreatic Ductal Adenocarcinoma Pathogenesis Pathway interactions Phosphoproteins Phosphorylation Premalignant Process Publishing Role SRC gene Signal Pathway Signal Transduction Stromal Cells Supporting Cell Surface System Testing Tissues Transforming Growth Factor beta Tyrosine Tyrosine Phosphorylation axon guidance cell motility cell stroma effective therapy epithelial to mesenchymal transition extracellular improved in vivo inhibitor/antagonist meetings mouse model mutant neoplastic cell new therapeutic target novel pancreatic neoplasm paracrine perineural public health relevance receptor research study response rho smoothened signaling pathway src-Family Kinases tumor tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) metastases are poorly understood, limiting the effectiveness of current treatments. An improved understanding of the mechanisms by which PDA metastasizes is critical for the development of effective treatments specific for this disease. We recently identified a PDA-associated antigen, annexin A2 (ANXA2), and demonstrated that tyrosine 23-phosphorylation-dependent cell-surface translocation of ANXA2 is critical for TGFbeta-Rho mediated epithelia-to-mesenchymal transition, invasion and metastasis of PDAs. This proposal aims to delineate the upstream and downstream pathways of ANXA2 to achieve our ultimate goal of identifying new therapeutic targets for PDA treatment. In particular, we hypothesize that two paracrine stromal-to-epithelial axes - the Hedgehog-Insulin-like growth factor I receptor pathway and the hepatocyte growth factor/c-met signaling - form a functional link between PDA stroma and epithelial compartments, resulting in ANXA2 phosphorylation. To understand the effector pathways whereby PDA metastases are promoted following the activation of ANXA2 by phosphorylation, our preliminary studies have led to the second part of our hypothesis that ANXA2 regulates PDA invasion and metastasis through Sema3d/Plxnd1, both belonging to an axon guidance pathway. We therefore propose two aims to test these hypotheses. Specific Aim 1 will elucidate the network of signals that originate in the stroma and result in ANXA2 translocation to the surface of PDA cells. Specific Aim 2 will delineate the downstream effectors of ANXA2 within PDA tumor cells that mediate metastatic spread through axon guidance molecules. The end result will be the elucidation of the complex network of signals that results in cross-talk between the PDA and its microenvironment, and that are mediated through ANXA2 to control PDA invasion and metastasis formation. This in turn, will provide new targets against which to develop novel interventions that disrupt the communication, and in doing so, abrogate tumor progression and metastases.

描述（由申请人提供）：人们对胰腺导管腺癌（PDA）转移知之甚少，限制了当前治疗的有效性。更好地了解 PDA 转移机制对于开发针对该疾病的有效治疗方法至关重要。我们最近鉴定了一种 PDA 相关抗原，膜联蛋白 A2 (ANXA2)，并证明 ANXA2 酪氨酸 23 磷酸化依赖性细胞表面易位对于 TGFbeta-Rho 介导的 PDA 上皮间质转化、侵袭和转移至关重要。该提案旨在描绘ANXA2的上游和下游通路，以实现我们确定PDA治疗新治疗靶点的最终目标。特别是，我们假设两个旁分泌基质到上皮轴 - 刺猬胰岛素样生长因子 I 受体途径和肝细胞生长因子/c-met 信号传导 - 在 PDA 基质和上皮区室之间形成功能联系，从而导致ANXA2 磷酸化。为了了解 ANXA2 磷酸化激活后促进 PDA 转移的效应途径，我们的初步研究得出了我们假设的第二部分，即 ANXA2 通过 Sema3d/Plxnd1 调节 PDA 侵袭和转移，两者都属于轴突引导途径。因此，我们提出两个目标来检验这些假设。具体目标 1 将阐明源自基质并导致 ANXA2 易位至 PDA 细胞表面的信号网络。具体目标 2 将描述 PDA 肿瘤细胞内 ANXA2 的下游效应器，通过轴突引导分子介导转移扩散。最终结果将阐明复杂的信号网络，这些信号导致 PDA 与其微环境之间的串扰，并通过 ANXA2 介导控制 PDA 侵袭和转移形成。反过来，这将提供新的目标，以开发新的干预措施来扰乱沟通，从而消除肿瘤的进展和转移。