The goal of this research proposal is to develop unique microarray-based assays to detect autoantibodies to glycopeptide epitopes of glycoproteins, and to evaluate their usefulness as diagnostic biomarkers for early detection of adenocarcinomas derived from different organ sites. We will also examine the expression of tumor associated glycan structures and mucin core proteins, in tissues of patients with early and late cancer.
Specific Aim 1. Test the hypothesis that autoantibody responses to tumor associated glycopeptide epitopes are useful as early diagnostic or prognostic markers for cancer. We will characterize the specificities of auto- antibodies using novel mucin based O-glycopeptide /glycoprotein arrays for screening sera from breast and pancreatic cancer patients,and serial samples of sera taken before diagnosis of cancer from women subsequently developing breast, ovarian, pancreatic and other carcinomas.
Specific Aim 2. Document the expression of cancer-associated mucin O-glycopeptide epitopes from early stage breast (including DCIS) and pancreatic cancer to invasive and metastatic disease, and correlate with the presence or absence of autoantibody responses to these epitopes to be analyzed as under Aim 1.
Specific Aim 3. Characterize expression of tumor associated glycans and glycosyltransferases in metastatic pancreatic cancer on a series of cases in which we have primary tumor and multiple metastatic sites obtained by rapid autopsy.
|Mirus, Justin E; Zhang, Yuzheng; Hollingsworth, Michael A et al. (2014) Spatiotemporal proteomic analyses during pancreas cancer progression identifies serine/threonine stress kinase 4 (STK4) as a novel candidate biomarker for early stage disease. Mol Cell Proteomics 13:3484-96|
|Liu, Xiang; Yi, Chunhui; Wen, Yunfei et al. (2014) Interactions between MUC1 and p120 catenin regulate dynamic features of cell adhesion, motility, and metastasis. Cancer Res 74:1609-20|
|Radhakrishnan, Prakash; Dabelsteen, Sally; Madsen, Frey Brus et al. (2014) Immature truncated O-glycophenotype of cancer directly induces oncogenic features. Proc Natl Acad Sci U S A 111:E4066-75|
|Burford, B; Gentry-Maharaj, A; Graham, R et al. (2013) Autoantibodies to MUC1 glycopeptides cannot be used as a screening assay for early detection of breast, ovarian, lung or pancreatic cancer. Br J Cancer 108:2045-55|
|Remmers, Neeley; Anderson, Judy M; Linde, Erin M et al. (2013) Aberrant expression of mucin core proteins and o-linked glycans associated with progression of pancreatic cancer. Clin Cancer Res 19:1981-93|
|Radhakrishnan, Prakash; Grandgenett, Paul M; Mohr, Ashley M et al. (2013) Expression of core 3 synthase in human pancreatic cancer cells suppresses tumor growth and metastasis. Int J Cancer 133:2824-33|
|Radhakrishnan, Prakash; Mohr, Ashley M; Grandgenett, Paul M et al. (2013) MicroRNA-200c modulates the expression of MUC4 and MUC16 by directly targeting their coding sequences in human pancreatic cancer. PLoS One 8:e73356|
|Mohr, Ashley M; Bailey, Jennifer M; Lewallen, Michelle E et al. (2013) MUC1 regulates expression of multiple microRNAs involved in pancreatic tumor progression, including the miR-200c/141 cluster. PLoS One 8:e73306|
|Schjoldager, Katrine T-B G; Vakhrushev, Sergey Y; Kong, Yun et al. (2012) Probing isoform-specific functions of polypeptide GalNAc-transferases using zinc finger nuclease glycoengineered SimpleCells. Proc Natl Acad Sci U S A 109:9893-8|
|Blixt, Ola; Lavrova, Olga I; Mazurov, Dmitriy V et al. (2012) Analysis of Tn antigenicity with a panel of new IgM and IgG1 monoclonal antibodies raised against leukemic cells. Glycobiology 22:529-42|
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