Mechanism behind CCL21/CCR7-mediated pancreatic cancer progression

CCL21/CCR7介导的胰腺癌进展机制

• 批准号: 9192473
• 负责人: Natasha A Moussouras
• 金额: $ 4.56万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192473
• 关键词: Adhesives; Animals; Area; Binding; Biological Assay; Breast; C-terminal; CCL21 gene; CXCR4 gene; Cell surface; Cells; Clinical; Colorectal; Combination Drug Therapy; Data; Dendritic Cells; Diagnosis; Disease; Distant; Doctor of Philosophy; Excision; Fellowship; Goals; Immune; Laboratories; Length; Ligands; Lung; Lymph; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mentorship; Metastatic Neoplasm to Lymph Nodes; Migration Assay; Modification; Molecular; Mus; Mutagenesis; NMR Spectroscopy; Neoplasm Metastasis; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Patients; Play; Polysialic Acid; Positive Lymph Node; Post-Translational Protein Processing; Process; Receptor Activation; Recurrence; Reporting; Role; Signal Transduction; Site; Structural Biologist; Structure; Sum; Survival Rate; Tail; Testing; Therapeutic; Time; Tissues; Tumor Cell Migration; United States; Variant; Work; base; cancer cell; cell motility; chemokine; chemokine receptor; chemotherapy; effective therapy; in vivo; insight; lymph nodes; migration; neoplastic cell; new therapeutic target; novel; novel strategies; outcome forecast; pancreatic cancer cells; prevent; receptor; release of sequestered calcium ion into cytoplasm; trafficking; training opportunity; tumor progression

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.

项目总结