All ETDs from UAB

Advisory Committee Chair

Susan L Bellis

Advisory Committee Members

Natalia Kedishvili

John Parant

Alexa Mattheyses

Karina Yoon

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


The upregulation of a certain subset of glycosyltransferases was an early marker for cancer development. Specifically, ST6Gal-I, which adds an α2-6 linked sialic acid to N-glycans on proteins bound for the plasma membrane or secretion, is selectively upregulated upon malignant transformation. Our laboratory has shown that ST6Gal-I is implicated in many facets of tumor biology and is an important mediator of tumorigenesis. For example, ST6Gal-I activity promotes the survival of cells when challenged with hypoxia, FasL, or TNFα, confers resistance to chemotherapeutics, enhances tumor cell migration and invasion, and fosters a cancer stem cell phenotype. The work presented in this dissertation adds to the fundamental understanding of ST6Gal-I’s function as a prosurvival factor and explores ST6Gal-I driven pancreatic cancer metastasis. Upon serum deprivation, ST6Gal-I expressing cells selectively survive by upregulating the activation of key prosurvival molecules NFκB and Akt. We also demonstrate that ST6Gal-I-expressing cells increase the expression of the cyclin D2 and phosphorylation of pRb, thereby allowing the cell cycle to proceed, despite limited access to growth factors. Accordingly, upon serum deprivation, cells expressing ST6Gal-I have a higher percentage of cells in S-phase in comparison to cells lacking ST6Gal-I. To understand the global effects of ST6Gal-I on the cell, we utilized an unbiased kinomics assay and report that ST6Gal-I expressing cells have elevated tyrosine kinase activity. Kinomics assay also revealed that EGFR is the most significantly altered tyrosine kinase, where ST6Gal-I enhances EGFR activation. To corroborate these findings, we tested three ovarian and pancreatic cancer cell lines and found that ST6Gal-I expressing cells have enriched ST6Gal-I-sialylated EGFR, therefore augmenting basal and ligand-induced activation. Furthermore, ST6Gal-I-mediated sialylation of EGFR protects against gefitinib mediated apoptosis. To better understand how sialylation affects EGFR, we investigated ST6Gal-I’s contribution to EGFR-driven epithelial to mesenchymal transition (EMT). These studies demonstrate that ST6Gal-I-mediated sialylation of EGFR confers a mesenchymal phenotype and mediates cellular invasion. Finally, we report that ST6Gal-I promotes pancreatic tumor growth and metastasis. The studies presented in this dissertation highlight the contribution of ST6Gal-I in promoting a metastatic cancer cell phenotype by enhancing survival signaling and pancreatic tumor progression.



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