Annexin A2 as a mediator of pancreatic cancer metastases

描述(申请人提供)：胰腺导管腺癌(PDA)转移知之甚少，限制了当前治疗的有效性。提高对PDA转移机制的了解对于开发针对这种疾病的有效治疗方法至关重要。我们最近发现了一种PDA相关抗原--膜联蛋白A2(Annexin A2，ANXA2)，并证实ANXA2的酪氨酸23磷酸化依赖的细胞表面易位在TGFbeta-Rho介导的上皮间充质转化、侵袭和转移中起关键作用。这项建议旨在勾勒出ANXA2的上游和下游通路，以实现我们的最终目标，即确定PDA治疗的新治疗靶点。特别是，我们假设两个旁分泌间质到上皮的轴-Hedgehog-Insulin-like生长因子I受体通路和肝细胞生长因子/c-met信号-在PDA间质和上皮室之间形成了功能联系，导致ANXA2磷酸化。为了了解在ANXA2被磷酸化激活后促进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，ANXA2通过Sema3d/Plxnd1调节PDA的侵袭和转移，两者都属于轴突导向途径。因此，我们提出了两个目标来检验这些假设。具体目标1将阐明起源于基质并导致ANXA2易位到PDA细胞表面的信号网络。具体目标2将描绘在PDA肿瘤细胞内通过轴突引导分子介导转移扩散的ANXA2下游效应器。最终结果将是阐明复杂的信号网络，这些信号网络导致PDA与其微环境之间的串扰，并通过ANXA2介导控制PDA的侵袭和转移形成。这反过来将提供新的靶点，针对这些靶点开发新的干预措施，以扰乱沟通，并在这样做的过程中，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.