ORCID ID
Graduation Date
Spring 5-9-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Biochemistry & Molecular Biology
First Advisor
Dr Moorthy P. Ponnusamy
Abstract
Despite critical advancements in cancer research, pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest malignancies worldwide. It is expected to be the second leading overall cause of cancer death in the United States by 2030. Aberrant glycosylation is a hallmark of cancer and has been implicated in tumor progression, immune evasion, and metastasis. However, its mechanistic contribution to organ-specific metastasis and its emerging roles beyond protein glycosylation remain incompletely understood. This dissertation investigates the role of glycosylation in PDAC progression through two complementary research avenues: glycosyltransferase-driven organotrophic metastasis and the emerging paradigm of RNA glycosylation.
First, we define the functional role of two specific glycosyltransferases in directing organ-specific metastatic behavior in PDAC. Using transcriptional profiling, genetic perturbation, in vitro functional assays, and in vivo metastatic models, we demonstrate that differential expression of glycosyltransferases, including GCNT3 and B3GNT3, is associated with liver- and lung-tropic metastatic phenotypes, respectively. Alterations in glycosyltransferase expression modulate glycoprotein landscapes, epithelial-mesenchymal transition programs, and metastatic colonization efficiency, highlighting glycosylation as a key regulator of metastatic organotropism.
The second part of this work explores RNA sialylation as a newly identified layer of post-transcriptional regulation in PDAC. Using metabolic labeling, Aptamer and RISH-based proximity labeling, chemical biology approaches, and glycomic analyses, we characterize cancer-associated alterations in sialoglycoRNA abundance and composition. Our findings reveal that RNA sialylation is differentially regulated in PDAC and is dependent on O-glycan biosynthetic pathways, suggesting functional crosstalk between classical glycosylation machinery and RNA biology.
Together, these studies establish glycosylation as a multifaceted regulator of PDAC progression, acting at both the protein and RNA levels to influence tumor behavior and metastatic potential. This work provides new mechanistic insights and lays the foundation for targeting glycosylation-dependent pathways as therapeutic and diagnostic strategies in pancreatic cancer.
Rights
The author holds the copyright to this work and any reuse or permissions must be obtained from the author directly.
Recommended Citation
Varadharaj, Venkatesh, "Glycoproteome and GlycoRNA Reprogramming in Pancreatic Cancer Progression and Metastasis" (2026). Theses & Dissertations. 1053.
https://digitalcommons.unmc.edu/etd/1053
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