Teams of the Alliance
Cummings/Ju Tumor Glycomics Laboratory
Principal Investigators: Richard D Cummings, PhD & Tongzhong
Ju, MD, PhD
Institution: Emory University, Atlanta, GA
Our project, The Tumor Antigens Tn and SialylTn in Human Colorectal Carcinoma, is a joint collaboration between our laboratories at Emory and with the laboratory of Dr. Lance Wells at the CCRC/University of Georgia.
In our studies we have found that colorectal cancer cells exhibit increased expression of a specific O-glycan biomarkers termed the Tn antigen, and its sialylated derivative SialylTn, which are found on numerous membrane glycoproteins and in secreted mucins. Expression of these antigens often occurs at an early stage of colon carcinogenesis, and is associated with poor prognosis and tumor metastasis; however, the molecular basis for expression of these antigens is not well understood. We recently found that expression of the Tn/SialylTn antigens can arise from loss-of-function of an enzyme termed the T-synthase, which required in all human cells for normal O-glycans biosynthesis. More importantly, we also found that expression of the T-synthase in turn requires the specific expression of a molecular chaperone we discovered and termed Cosmc. The Cosmc gene is on the X-chromosome and we found that spontaneous, acquired mutations or copy loss of this gene can occur in tumor cells and is associated with decreased expression of the T-synthase and consequent expression of the Tn/SialylTn antigens. We believe that the abnormal expression of these antigens, which are not usually found on any normal glycoproteins in humans, is associated with altered glycoprotein functions, cell signaling, and adhesion, all of which may contribute to tumor progression and metastasis. Our preliminary studies also show that gastrointestinal tract epithelial cell-specific loss of Cosmc in mice causes Tn/SialylTn antigen expression in the small and large intestine.
In our studies supported by the Alliance of Glycobiologists for Detection of Cancer, we are exploring the hypothesis that Tn/SialylTn tumor antigens in colorectal carcinomas are novel glycan biomarkers for human colon cancer and arise from alterations in Cosmc or altered expression of T-synthase. Thus, we are studying the molecular basis for the expression of Tn/SialylTn and other tumor-associated carbohydrate antigens in human primary colon tumors, defining the glycan and glycopeptide profiles of colorectal carcinoma cells compared to normal cells to identify protein carriers of the Tn/Sialyl Tn antigens, as well as defining the molecular mechanism(s) for Tn/SialylTn expression in human primary colon tumors by identifying the alterations in Cosmc, and expression of other perhaps relevant related “glycogenes”. Finally, we are also developing well-defined monoclonal antibodies that exhibit both high specificity and affinity to Tn or SialylTn antigens, which could be used in both diagnosis and treatment of colorectal carcinoma.
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