A unique glycan is a specific marker for pancreatic adenocarcinoma
Dolezal, Samuel Joseph
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Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers with one-year and five-year survival rates of only 24% and 5%, respectively. Physicians currently lack useful biomarkers in the screening, diagnosis, and treatment of PDAC, which unfortunately leads to the majority of patients being diagnosed in incurable, progressive stages or after metastasis has already occurred. Glycan structures expressed on glycoproteins are dynamic; quantitative and qualitative alternation of glycan expression is a hallmark of oncogenesis. These glycosylation changes are found on cell surface glycoconjugates and, in one case, has been specifically targeted as a therapeutic strategy. To identify a cancer-specific glycan target for PDAC, a mouse monoclonal IgG antibody (MAb109) has been identified that reacts with PDAC, but not with non-diseased pancreatic tissues. The epitope of this antibody is an N-glycan-specific epitope expressed on a small set of glycoproteins, as demonstrated by N-Glycosidase F (PNGaseF) sensitivity on immunoblots following SDS-PAGE. The specific glycoprotein in PDAC that expresses the epitope is CEACAM6, CD66c. Mass spectrometric analysis (MS) analysis performed on MAb-reactive CEACAM6 tryptic glycopeptides identified the epitope as an additional HexNAc attached to the β-linked core mannose, which was expressed only on one out of 12 N-linked sites. Additionally, truncation and site-directed mutagenesis identified three consecutive amino acids toward the C-terminus of CEACAM6 that function as a sequence determinant required for addition of the glyan epitope at its upstream glycosylation site. This determinant explains the stringent specificity of the epitope for expression on CEACAM6 and, in some cancers, CEACAM5, which has significant sequence identity with CEACAM6. MAb109 that targets this unique glycan epitope may demonstrate potential as a therapeutic for PDAC, while the epitope, which is released from PDAC cells, may serve as a potential diagnostic for this disease.