Pancreatic cancer is expected to cause >32,000 deaths in he United States this year. This high mortality is largely due to lack of reliable methods for early tumor detection, and lack of treatment options that produce a cure. One complication with traditional cancer treatments is that they can easily miss the small subset of cells, termed stem cells, which have been shown to be responsible for a tumor's ability to proliferate. Aberrant protein glycosylation is linked to the onset and progression of cancer. Particularly, acidic glycans with sialic acid and sulfate groups are often altered. Interestingly, recently identified cell surface markers of pancreatic cancer stem cells are glycoproteins. However, due to tremendous analytical challenges associated with structural determination of labile, heterogeneous and branched glycans, detailed cancer-associated glycan structures, which are required for generation of novel diagnostics and therapeutics, including cancer vaccines, are scarce. Mass spectrometry (MS) can provide sensitive and accurate glycan analysis. However, a major challenge in acidic molecule MS is low ionization efficiency. A second challenge is the determination of saccharide branching and specific linkage. Also, sialic acids and sulfate groups are extremely labile, further compromising ionization and rendering sulfate localization difficult. This application focuses on developing novel MS approaches for identifying and structurally characterizing glycans uniquely expressed by pancreatic cancer stem cells (potential biomarkers). Specifically, zirconia and titania surface chemistry will be utilized to enrich sialylated and sulfated glycans from complex mixtures, thereby greatly improving their detection by nano-scale normal phase liquid chromatography Fourier transform ion cyclotron resonance (FTICR) MS. For structural determination of these glycans, we will utilize metal-assisted electron capture dissociation, electron detachment dissociation, and vacuum ultraviolet photodissociation, respectively, to increase sugar cross-ring cleavage, which provides linkage information and therefore allows determination of branched structures, and to determine sulfate location.

Public Health Relevance

Pancreatic cancer is a major death cause in the United States with a five-year survival rate of <5%. This research focuses on developing novel approaches for improved detection and structural determination of carbohydrates (sugar molecules) present on the surface of pancreatic cancer stem cells, that is, a subset of cells within a tumor that is responsible for its ability to grow and propagate. Carbohydrates are known to be altered in cancer and therefore constitute promising targets for cancer vaccine development.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRLB-Q (J1))
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Knowlton, John R
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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