Mechanism behind CCL21/CCR7-mediated pancreatic cancer progression

项目摘要 胰腺癌是一种毁灭性的疾病，生存率极低，特别是对于那些 在诊断时存在转移。不幸的是手术和联合化疗 并没有在生存方面取得重大进展。因此，迫切需要新的治疗方法。 由于转移，特别是淋巴结转移，通常是复发和不良反应的原因。 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。 转移的过程涉及肿瘤细胞迁移到新的部位。趋化因子通常 引导细胞从一个组织迁移到另一个组织。这个过程可以被肿瘤细胞劫持， 淋巴结和远处转移。趋化因子配体-受体对，CCL 21和CCR 7，指导 免疫细胞向淋巴结的运输。CCR 7在许多癌症中表达增加， 与淋巴结转移和预后不良有关。有趣的是，CCL 21在结构上是独特的， 由于长的C-末端尾可能抑制其与其受体CCR 7的相互作用， 时尚.此外，翻译后修饰聚唾液酸，分别显示与 转移，已经被认为是减轻CCL 21的自身抑制的试剂。在一起，这三个 CCR 7、CCL 21和聚唾液酸，每一种都分别与癌症转移有关， 这两个因素构成了这一提议的基础。 本研究的目的是检验聚唾液酸化CCR 7与CCL 21结合介导 胰腺癌淋巴结转移实现这一目标将通过两个目标来实现。 目的1将采用核磁共振光谱学，通过检查结构，深入研究自抑制机制， CCR 7上的聚唾液酸与CCL 21的C末端之间的相互作用。目标2将使用以下组合： 除了体内动物研究之外，还进行了信号传导和迁移测定，以研究这些信号传导和迁移的功能作用。 在胰腺癌的淋巴结转移中起重要作用。利用以下方面的互补关系： 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.