Date of Award
Spring 4-2-2024
Embargo Period
4-2-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cell and Molecular Pharmacology and Experimental Therapeutics
College
College of Graduate Studies
First Advisor
Richard R. Drake
Second Advisor
Anand S. Mehta
Third Advisor
Peggi M. Angel
Fourth Advisor
Amy D. Bradshaw
Fifth Advisor
Monika Gooz
Abstract
Prostate Cancer (PCa) poses a significant clinical challenge, characterized by debates on screening efficacy and continuous issues with distinguishing aggressive from non-aggressive tumors. Despite treatment advancements, poor patient outcome at late stages and clinical overtreatment of indolent disease emphasizes the urgent need for markers of PCa aggression. Aberrant glycosylation and extracellular matrix (ECM) remodeling are two complex molecular processes necessary for PCa progression, highlighting a novel area for biomarker discovery. Leveraging formalin-fixed paraffin-embedded tissues, tissue microarrays (TMAs), and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), distinct N-glycan and ECM profiles are identified. Elevated bisecting, multi-antennary, and fucosylated N-glycans indicate early signs of increased risk for PCa metastasis in a novel patient outcome TMA cohort. Serial enzymatic digests of tissues revealed samples rich in N-glycans with core-fucose modifications, specifically, exhibited greater risk for eventual metastasis. Further analysis of large tissue samples from which TMAs were derived revealed a unique spatial distribution of these N-glycans of interest throughout both tumor and tumor-adjacent microenvironments, providing novel vi insight into the roles of these structures in disease progression. In further pursuit of increased fucosylation as a marker for PCa aggression, analysis of a TMA constructed from tissues with heightened risk of neuroendocrine differentiation and castrate-resistance revealed a greater abundance of fucosylated N-glycans. Investigating differences in ECM composition between tissue samples from PCa that eventually metastasized and PCa that never recurred sheds light on potential prognostic markers that have potential to improve patient outcome. Proteomic analysis of these tissues revealed several protein species exclusive to PCa at risk for metastasis. These biomarkers hold transformative implications for tailoring patient-centric treatment strategies and foster a comprehensive understanding of disease dynamics at a molecular level.
Recommended Citation
Hartig, Jordan, "MALDI-MSI Identification of Tissue-Level N-Glycomic and Proteomic Molecular Biomarkers of Aggressive Prostate Cancer" (2024). MUSC Theses and Dissertations. 849.
https://medica-musc.researchcommons.org/theses/849
Rights
Copyright is held by the author. All rights reserved.