The focus of this proposal is to develop further potential glycomarkers we have identified for pancreatic cancer and breast cancer, as well as to discover new glycomarkers by detailed glycomic analysis of the tumor initiating cells (TIC) of pancreatic and breast cancer and of tumor-associated """"""""stellate"""""""" cells that surround pancreatic cancer. Clearly, developing biomarkers for pancreatic and breast cancer is of critical importance in the early detection of cancers. During the first cycle of the NCI U01 focused on Glycans and Cancer, we analyzed pancreatic ductal fluid from those with pancreatic ductal adenocarcinoma and controls using glycomic analysis tools developed in our NCRR Resource for Biomedical Glycomics. We have identified several potential glycomarkers that will be developed in this competitive renewal application. Most notably, we have identified a unique N-glycan that shows promise as a sensitive and specific marker of pancreatic adenocarcinoma. In addition, we developed a Targeted Glycoproteomics technology and used it to identify potential markers in invasive ductal breast carcinoma tissue. Two glycoprotein glycomarkers were identified and verified in serum samples. A newly devised sandwich ELISA to detect the specific glycoform of one of these markers shows promise in distinguishing serum from patients with breast cancer and those with benign polycystic disease. In the discovery Aim of this proposal, we will prepare TIC from pancreatic adenocarcinoma by cell sorting and apply glycomics technologies to identify differences between TIC and differentiated tumor cells. A similar strategy will be utilize using cultured breast cancer cell lines. As we have during the first cycle of the U01, we will exploit these differences by devising serum assays to identify potential glycoprotein glycoform markers. Similarly, we will analyze tumor-associated fibroblastic """"""""stellate"""""""" cells from pancreatic cancers and grown in culture for potential glycomarkers. These cells surround these cancers and may, therefore, secrete or release potential glycomarkers for the cancer that can be detected in serum.
The studies in this proposal will both develop potential glycan biomarkers for pancreatic and breast cancer that we have developed over the first time-frame of the U01, as well as discover new glycomarkers for two specific types of cells in these tumors. These cells are either thought to function in the initiation of tumors, called tumor-initiating cels, or surround them, called tumor-associated stellate cells. Validation of any of the potential glycomarkers originating in our work could have a significant impact on the early diagnosis of cancer.
|Carvalho, S; Catarino, T A; Dias, A M et al. (2016) Preventing E-cadherin aberrant N-glycosylation at Asn-554 improves its critical function in gastric cancer. Oncogene 35:1619-31|
|Durning, Sean P; Flanagan-Steet, Heather; Prasad, Nripesh et al. (2016) O-Linked Î²-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells. J Biol Chem 291:2107-18|
|Guo, Huabei; Abbott, Karen L (2015) Functional impact of tumor-specific N-linked glycan changes in breast and ovarian cancers. Adv Cancer Res 126:281-303|
|Whatcott, Clifford J; Diep, Caroline H; Jiang, Ping et al. (2015) Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer. Clin Cancer Res 21:3561-8|
|Whatcott, Clifford J; Han, Haiyong; Von Hoff, Daniel D (2015) Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer: Normalization, Not Destruction. Cancer J 21:299-306|
|Cummings, Richard D; Pierce, J Michael (2014) The challenge and promise of glycomics. Chem Biol 21:1-15|
|Vaidyanathan, Krithika; Durning, Sean; Wells, Lance (2014) Functional O-GlcNAc modifications: implications in molecular regulation and pathophysiology. Crit Rev Biochem Mol Biol 49:140-63|
|Porterfield, Mindy; Zhao, Peng; Han, Haiyong et al. (2014) Discrimination between adenocarcinoma and normal pancreatic ductal fluid by proteomic and glycomic analysis. J Proteome Res 13:395-407|
|Dolezal, Samuel; Hester, Shanterian; Kirby, Pamela S et al. (2014) Elevated levels of glycosylphosphatidylinositol (GPI) anchored proteins in plasma from human cancers detected by C. septicum alpha toxin. Cancer Biomark 14:55-62|
|Guo, Huabei; Nagy, Tamas; Pierce, Michael (2014) Post-translational glycoprotein modifications regulate colon cancer stem cells and colon adenoma progression in Apc(min/+) mice through altered Wnt receptor signaling. J Biol Chem 289:31534-49|
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