ORCID ID
Graduation Date
Summer 8-14-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Interdisciplinary Graduate Program in Biomedical Sciences
First Advisor
Michael A. Hollingsworth
Second Advisor
Joyce Solheim
Third Advisor
Gloria Borgstahl
Fourth Advisor
Nicholas Woods
Abstract
Pancreatic cancer is a highly lethal disease with immense metastatic potential. Its poor survival stems primarily from our lack of mechanistic understanding of its underlying biology. Pancreatic cancer cells utilize extracellular vesicles (EVs) to promote protumorigenic signaling and reprogram the tumor microenvironment (TME). EVs are essential for normal cellular communication; however, when cancer cells hijack their transport properties, they facilitate pre-metastatic niche formation. Transmembrane glycoprotein Mucin1 (MUC1) is a key mediator of pancreatic cancer progression and EV biogenesis due to its diverse signaling portfolio, interacting with numerous cancer-related pathways. However, despite substantial research on MUC1 in this context, including its overexpression in cancer and cancer-derived EVs, there remains limited understanding of mechanisms behind this substantial influence on tumor progression. In our published work, we presented the first known association between MUC1 and EV-related protein ALIX. Our findings show MUC1 influences EV cargo packaging through ALIX association, introducing a potentially novel regulatory mechanism of EV biogenesis in pancreatic cancer. In this dissertation, I present integrated findings testing this mechanism through biochemistry, structural and cancer biology, and clinical translation. I developed the first recombinant purification of MUC1’s intrinsically disordered cytoplasmic tail, overcoming immense solubility challenges and enabling biochemical and structural investigation of its protein interaction function, and presented the first evidence of direct MUC1CT-ALIX binding in the absence of cellular content, revealing sub-nanomolar affinity binding (Chapter 2). I furthered this by biochemically and structurally defining a key interaction motif that undergoes conformational changes upon MUC1CT-ALIX binding, providing protease protection and thermal stabilization, while identifying a potentially new binding pocket within ALIXBro1 (Chapter 3). I then evaluated how diabetes influences MUC1-elevated inflammatory signatures in pancreatic neuroendocrine tumors, revealing key pathways related to epithelial-to-mesenchymal transition, extracellular matrix remodeling, and immune-related changes (Chapter 4). Together, these findings present my work over the past 5 years detailing how MUC1 orchestrates EV cargo sorting and TME remodeling through ALIX interaction, redefining our understanding of EV-driven pancreatic cancer progression and establishing a targetable interface for future therapeutic intervention to improve survival in this devastating disease.
Rights
The author holds the copyright to this work and any reuse or permissions must be obtained from the author directly.
Recommended Citation
Hoagstrom, Kristine V., "Mucin1 in Extracellular Vesicle Biology and Pancreatic Cancer: Mechanistic Roles and Disease Relevance" (2026). Theses & Dissertations. 1098.
https://digitalcommons.unmc.edu/etd/1098