Mechanism behind CCL21/CCR7-mediated pancreatic cancer progression

项目总结 胰腺癌是一种毁灭性的疾病，存活率低得令人难以置信，特别是对于那些 在诊断时出现转移。不幸的是，手术和联合化疗 在生存方面没有取得重大进展。因此，迫切需要新的治疗方法。 因为转移，特别是淋巴结转移，往往是复发和不良的原因 预后，阐明转移背后的机制可以提供宝贵的信息和新的 胰腺癌的治疗靶点。 转移的过程包括肿瘤细胞迁移到新的部位。趋化因子正常 引导细胞从一个组织迁移到另一个组织。这一过程可以被肿瘤细胞劫持，从而 转移到淋巴结和远处的部位。趋化因子配体-受体对CCL21和CCR7指导 免疫细胞向淋巴结流动。CCR7在许多癌症中表达增加，并已 与淋巴转移和预后不良有关。有趣的是，CCL21在结构上是独特的 由于长的C末端尾巴可能在自身抑制中抑制其与其受体CCR7的相互作用 时尚。此外，翻译后修饰的聚唾液酸，单独显示与 转移，已被认为是解除CCL21的S自身抑制的药物。加起来，这三个人 分别与癌症转移有关的成分CCR7、CCL21和聚唾液酸是 结合在一起，形成了这项建议的基础。 这项研究的目标是检验这样一种假设，即多唾液酸化的CCR7与CCL21结合后， 胰腺癌的淋巴转移。这一目标的实现将通过两个目标来实现。 目标1将使用核磁共振波谱通过检查结构来深入研究自抑制的机制 CCR7上聚唾液酸与CCL21 C末端的相互作用《目标2》将结合使用 信号和迁移分析，除了活体动物研究，以研究这些功能的作用 胰腺癌淋巴转移的相关因素。利用两国之间的互补关系 通过完成这两个目标的结构和功能将提供关于一种新的机制的细节，该机制可以 有针对性地开发针对这种高度侵袭性疾病的治疗方法。

PROJECT SUMMARY Pancreatic cancer is a devastating disease with incredibly low survival rates, especially for those who present with metastases at the time of diagnosis. Unfortunately, surgery and combination chemotherapies have not made significant advances in survival. As such, novel approaches to therapy are desperately needed. Since metastases, and specifically lymph node metastases, are often responsible for recurrence and poor prognosis, elucidating the mechanism behind metastasis can provide invaluable information and a new therapeutic target in pancreatic cancer. The process of metastasis involves the migration of tumor cells to new sites. Chemokines normally direct the migration of cells from one tissue to another. This process can be hijacked by tumor cells, allowing metastasis to lymph nodes and distant sites. The chemokine ligand-receptor pair, CCL21 and CCR7, direct the traffic of immune cells towards the lymph nodes. CCR7 has increased expression in many cancers and has been associated with lymph node metastasis and worse prognosis. Interestingly, CCL21 is structurally unique due to a long C-terminal tail that may be inhibiting its interaction with its receptor CCR7 in an autoinhibitory fashion. Furthermore, the post-translational modification polysialic acid, shown separately to correlate with metastasis, has been implicated as the agent that relieves CCL21's autoinhibition. Together, these three components, CCR7, CCL21, and polysialic acid, each separately implicated in cancer metastasis, are combined to form the basis of this proposal. The goal of this fellowship is to test the hypothesis that polysialylated CCR7 binding to CCL21 mediates lymph node metastasis in pancreatic cancer. The pursuit of this goal will be accomplished through two aims. Aim 1 will employ NMR spectroscopy to delve into the mechanism of autoinhibition by examining the structural interactions between polysialic acid on CCR7 and the C-terminus of CCL21. Aim 2 will use a combination of signaling and migration assays, in addition to in vivo animal studies, to study the functional role of these players in lymph node metastasis in pancreatic cancer. Exploiting the complementary relationship between structure and function through completion of these two aims will provide details on a novel mechanism that can be targeted to develop therapeutics against this highly aggressive disease.