All ETDs from UAB

Advisory Committee Chair

Susan L Bellis

Advisory Committee Members

Karen Hardiman

Alexa Mattheyses

Document Type

Thesis

Date of Award

2023

Degree Name by School

Master of Science (MS) Heersink School of Medicine

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year survival of ~10%. Recent studies in the US population suggest PDAC as the fourth leading cause of cancer-related deaths in 2022. ST6 β-galactoside α2,6-sialyltransferase (ST6GAL1) is a glycosyltransferase which is known to be upregulated in cancer. It acts as a master regulator of a cell by being the predominant sialyltransferase catalyzing the addition of a bulky negatively charged sialic acid to the galactose sugar in an α2,6-linkage. Due to this, the sialic acid changes the structure and function of cell surface receptor proteins and regulates signal transduction and consequently, the cell phenotype. Moreover, given that this enzyme is upregulated in cancer and our preliminary data shows that ST6GAL1 drives the cell towards a more Acinar to Ductal Metaplasia-like phenotype, I hypothesize that expression of ST6GAL1 promotes stem-like cell behaviors, such as enhanced survival and invasiveness, thereby promoting neoplasia. This hypothesis predominantly focuses on the transition between normal pancreatic acinar to tumor cell and the importance of ST6GAL1 in the tumor initiation process on which few studies have been reported. This study utilizes proliferation assays, clonogenic assays, death assays and soft agar colony formation assays using murine pancreatic acinar cancer cells and immortalized normal human pancreatic acinar cells to demonstrate ST6GAL1 influencing stem-like cell behaviors in vitro. To demonstrate cell behaviors in vivo, pancreatitis mouse model with overexpressing ST6GAL1 was created, and immunofluorescent staining was done on pancreas tissue samples. Overexpression of ST6GAL1 resulted in not only, increased proliferation and colony formation but iv also, decreased cell death when treated with IFN-γ and TNF-α. Also, the results showed that overexpression of ST6GAL1 increases anchorage independent growth. Overall, the results showed that overexpression of ST6GAL1 provides the cells with a greater proliferative, pro-survival and invasive phenotype. Given the lethality of PDAC, there is a need to identify new molecular targets for effective treatment. This study successfully uncovers cell behaviors that promote the transition from ADM to neoplasia, offering novel avenues to inhibit PDAC progression.

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