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2009 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report We work with clinical collaborators at several institutions to address various clinical needs. One such need is to help doctors make a more accurate diagnosis of patients with suspected pancreatic cancer. Since pancreatic cancer can be difficult to distinguish from benign conditions of the gastrointestinal tract, highly accurate biomarkers are needed to match patients to the appropriate procedures at the earliest possible time. We also are developing biomarkers to screen for clinically undetectable pancreatic cancer. Among populations at an increased risk for developing pancreatic cancer—including those suffering from chronic pancreatitis or with a family history of pancreatic cancer—an accurate screening test could detect new cancers early enough to allow more effective treatment. Further, we are testing our novel biomarkers for use in drug trials. Biomarkers that give early indications of the effectiveness of a candidate drug could accelerate drug trials and better match patients with the drugs that benefit them most. Another novel class of biomarker we are developing is for the diagnosis of patients with pancreatic cysts. Cystic lesions of the pancreas are increasingly being recognized due to the widespread use of high-resolution abdominal imaging. Since certain cyst types are precursors of invasive cancer, this situation presents an opportunity to intervene prior to malignant progression. Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions based on differences in their malignant potential. In collaboration with Dr. Diane Simeone at the University of Michigan, we have identified glycan variants of secreted mucins that distinguish benign from pre-cancerous cysts with an 87% accuracy—better than the best current markers. Ongoing work is aimed at validating and building upon these results. Ultimately, we hope to implement a test that could be used to determine which pancreatic cysts should be surgically removed in order to prevent progression to cancer. Origin and function of secreted glycan alterations in pancreatic cancer Our laboratory also studies the origins and functions of cancer-cell secretions bearing altered glycans. The carbohydrate alterations observed in pancreatic tumors are strongly associated with accelerated disease progression, but it is not known whether these alterations functionally contribute to that progression. We have shown that certain glycoprotein alterations Figure 2 are likely the product of subpopulations of tumor cells that are more likely to be aggressive. Using ALSA in a study of cultured pancreatic cancer cells, we have shown that cells bearing markers of high tumor-forming capability (termed “cancer stem cell markers”) display distinct glycan characteristics. The glycans of such cancer cells are distinctly altered in response to inflammatory signaling from the environment, showing the link between secreted glycan structures and the cellular state. Additional studies have shown distinct glycan alterations produced when cells transition from a stationary to a migratory state. This transition initiates metastasis and results in tumors at new sites. This work clearly links the origin of particular cancer-associated glycans with aggressive cancer cells. Figure 2. Distinct changes to glycan levels associated with cell type. Cell lines were treated with various pro-inflammatory signals, including oxidative stress (H 2 O 2 ) and the cytokines IFNg, TNFa, or IL-a1. The cell lines and their treatments are indicated by the column labels. Six cell lines were treated: two bearing cell-surface markers characteristic of tumorigenicity (labeled in red); two not bearing the markers (labeled in black); and two partially bearing the markers (labeled in green). Using the ALSA assay, the levels of various glycans on the mucins MUC1, MUC5AC, and MUC16 in the secretions of the cells were measured before and after treatment. The row labels indicate the lectin used for detection (which determines the glycan detected) and the capture antibody. The color of each square represents the fold-change of the signal after treatment divided by the signal before treatment. The cells bearing markers of tumorigenicity uniquely increased particular glycans, showing a difference from the other cells in their glycan characteristics. 28

VARI | 2009 We are pursuing the hypothesis that the distinct glycans and glycoproteins secreted by aggressive or tumor-initiation cancer cells contribute to cancer progression through interactions with cells and proteins of the tumor environment. Evidence from our laboratory suggests that these secretions produce a higher state of inflammation and weaker immune recognition of the cancer cells. Our goals are to characterize the glycan alterations and their protein carriers that are unique to aggressive subsets of cancer cells and to understand the mechanisms by which these molecules affect host cells and promote tumor progression. In addition, we are investigating new strategies for treating cancer based on these observations. Targeting the functions of the aggressive subpopulations of cancer cells could be highly effective. External Collaborators Michelle Anderson, Philip Andrews, Dean Brenner, Irwin Goldstein, Venkat Keshamouni, Gilbert Omenn, and Diane Simeone, University of Michigan, Ann Arbor Randall Brand and Anna Lokshin, University of Pittsburgh, Pennsylvania William Catalona, Northwestern University, Evanston, Illinois Terry Du Clos, University of New Mexico, Albuquerque Ziding Feng and Samir Hanash, Fred Hutchinson Cancer Research Center, Seattle, Washington Weimin Gao, Texas Tech University, Lubbock William Hancock, Northeastern University, Boston, Massachusetts Michael A. Hollingsworth, University of Nebraska, Omaha Raju Kucherlapati, Harvard Medical School, Boston, Massachusetts Recent Publications Wu, Yi-Mi, and Brian. Haab. In press. The nature and function of glycan alterations in pancreatic cancer. In Drug Discovery in Pancreatic Cancer: Models and Techniques, Haiyong Han and Paul Grippo, eds. Springer Verlag. Hung, K.E., V. Faca, K. Song, D. Sarracino, L.G. Richard, B. Krastins, S. Forrester, A. Porter, A. Kunin, U. Mahmood, B.B. Haab, et al. 2009. Comprehensive proteome analysis of an Apc mouse model uncovers proteins associated with intestinal tumorigenesis. Cancer Prevention and Research 2(3): 224–233. Wu, Yi-Mi, D. David Novack, Gilbert S. Omenn and Brian B. Haab. 2009. Mucin glycosylation is altered by pro-inflammatory signaling in pancreatic cancer cells. Journal of Proteome Research 8(4): 1876–1886. Yue, Tingting, and Brian B. Haab. 2009. Microarrays in glycoproteomics research. Clinics in Laboratory Medicine 29(1): 15–29. Chen, S., and B.B. Haab. 2008. Antibody microarrays for protein and glycan detection. In Clinical Proteomics, J. Van Eyk and M. Dunn, eds. Weinheim, Germany: Wiley-VCH. From left: Sinha, Antecki, Wu, Haab, Nelson, Maupin, VanOcker, Babins, Kluck, Yue 29

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