Annexin A2 as a mediator of pancreatic cancer metastases

描述（由申请人提供）：胰腺导管腺癌（PDA）转移的了解很少，限制了目前治疗的有效性。进一步了解PDA转移的机制对于开发针对这种疾病的有效治疗方法至关重要。我们最近鉴定了PDA相关抗原，膜联蛋白A2（ANXA 2），并证明ANXA 2的酪氨酸23-磷酸化依赖性细胞表面易位对于TGF β-Rho介导的PDA上皮向间充质转化、侵袭和转移至关重要。该提案旨在描述ANXA 2的上游和下游途径，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基质-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基质和上皮隔室之间形成功能性联系，导致ANXA 2磷酸化。为了了解ANXA 2通过磷酸化激活后促进PDA转移的效应途径，我们的初步研究导致了我们假设的第二部分，即ANXA 2通过Sema 3d/Plxnd 1调节PDA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测试这些假设。特异性目的1将阐明起源于基质并导致ANXA 2易位至PDA细胞表面的信号网络。特异性目标2将描绘PDA肿瘤细胞内ANXA 2的下游效应物，其通过轴突引导分子介导转移性扩散。最终结果将是阐明导致PDA与其微环境之间的串扰的复杂信号网络，以及通过ANXA 2介导以控制PDA侵袭和转移形成的信号网络。这反过来将提供新的靶点，以开发新的干预措施来破坏通信，并在此过程中消除肿瘤进展和转移。

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.