Induced Glycan Alterations in Sub-populations of Pancreatic Tumors

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DESCRIPTION (provided by applicant): Glycan alterations are known to be critical for several processes that contribute to cancer progression, particularly in pancreatic cancer, where glycosylation alterations are highly prevalent. Little is known about the conditions that give rise to those alterations, or whether they distinctly occur in particular subpopulations of cancer cells. Preliminary data have shown that pro-inflammatory cytokine signaling induces glycan alterations in pancreatic cancer cells, suggesting the possibility that the inflammatory environment typically seen in pancreatic cancer induces cancer cells to modify their extracellular glycan structures. Furthermore, the preliminary data suggest that the induced glycan alterations are different between groups of cell lines, as defined by the presence or absence of cell-surface markers that are associated with tumorigenicity in pancreatic cancer. That finding suggests that induced glycan alterations are distinct between cell types, and that these glycan alterations contribute to the particular behavior of each cell type. In order to gain insight into the relevance of these behaviors to cancer biology, the next step is to investigate these hypotheses in primary tumor cells, rather than in the cell line models used for the preliminary studies. A good system for that work is mouse xenografts from human primary tumors, which have been established for pancreatic cancer and can provide enough material for experiments on sorted cell subpopulations. In the first aim, we will determine whether the glycosylation or expression status of several mucins is different between the tumorigenic and non-tumorigenic subpopulations. In the second aim, we will determine whether these subpopulations display different glycan alterations in response to cytokine signaling. A significant aspect of this project is the unique experimental approach of using antibody arrays with glycan detection to measure protein and glycan variation on several specific proteins. The micro-scale nature of that assay also is valuable for the study of small subpopulations of cells. This work is well suited to a pilot-project mechanism since it will give insights into a possibly transformative research direction. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a devastating disease with very low survival rates. It is known that alterations to the carbohydrates on the surfaces of cancer cells are important for disease progression, but the factors that give rise to those alterations, and the particular cancer cell types on which they appear, are incompletely understood. This proposal addresses that question, which has implications for treating or controlling pancreatic cancer.