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.
Pancreatic cancer is the fourth most deadly cancer in the United States, with over 90% of those diagnosed succumbing to the disease within five years. Early and elusive metastases are often to blame, with CCL21, CCR7, and polysialic acid emerging as key players in lymph node-directed cell migration. The precise mechanism by which the CCL21/CCR7/polysialic acid axis drives lymph node metastasis is unknown, but will be explored in this fellowship.
| Moussouras, Natasha A; Getschman, Anthony E; Lackner, Emily R et al. (2017) Differences in Sulfotyrosine Binding amongst CXCR1 and CXCR2 Chemokine Ligands. Int J Mol Sci 18: |
| Phillips, Andrew J; Taleski, Deni; Koplinski, Chad A et al. (2017) CCR7 Sulfotyrosine Enhances CCL21 Binding. Int J Mol Sci 18: |
| Smith, Emmanuel W; Lewandowski, Eric M; Moussouras, Natasha A et al. (2016) Crystallographic Structure of Truncated CCL21 and the Putative Sulfotyrosine-Binding Site. Biochemistry 55:5746-5753 |
