Annexin A2 as a mediator of pancreatic cancer metastases

描述（由申请人提供）：胰腺导管腺癌（PDA）转移尚不清楚，限制了当前治疗的有效性。提高对PDA转移机制的理解对于开发针对该疾病的有效治疗方法至关重要。我们最近发现了一种与pda相关的抗原，膜联蛋白A2 (ANXA2)，并证明酪氨酸23-磷酸化依赖的ANXA2的细胞表面易位对于tgf - rho介导的pda的上皮到间质转化、侵袭和转移至关重要。本提案旨在描述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-上皮轴——刺猬胰岛素样生长因子I受体通路和肝细胞生长因子/c-met信号通路——在PDA基质和上皮间室之间形成功能联系，导致ANXA2磷酸化。为了了解在磷酸化激活ANXA2后促进PDA转移的效应通路，我们的初步研究导致了我们假设的第二部分，即ANXA2通过Sema3d/Plxnd1调节PDA的侵袭和转移，这两个通路都属于轴突引导通路。因此，我们提出两个目标来检验这些假设。特异性目的1将阐明源自基质并导致ANXA2易位到PDA细胞表面的信号网络。特异性Aim 2将描述通过轴突引导分子介导转移扩散的PDA肿瘤细胞中ANXA2的下游效应物。最终的结果将是阐明导致PDA与其微环境之间的串扰的复杂信号网络，并通过ANXA2介导控制PDA的侵袭和转移形成。反过来，这将提供新的靶点，开发新的干预措施，破坏通信，并在这样做，消除肿瘤的进展和转移。

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.