Graduation Date

Spring 5-4-2024

Document Type


Degree Name

Doctor of Philosophy (PhD)


Interdisciplinary Graduate Program in Biomedical Sciences

First Advisor

Dr. Sushil Kumar


Pancreatic cancer is characterized by a stroma component that comprises up to 90% of the tumor. Cancer-associated fibroblasts (CAFs) are a significant component of the stroma and contribute to cancer pathobiology through the secretion of extracellular matrix, growth factors, metabolites, and cytokines. CAFs are a highly heterogeneous population derived from various precursors, including adipose-derived and bone marrow- derived mesenchymal stem cells (AD-MSCs, BM-MSCs) and pancreatic stellate cells (PSCs). In this dissertation, we examine how mucin 5ac (Muc5ac) mediates the maturation of AD-MSCs, BM-MSCs, and PSCs into CAFs and the heterogeneity between CAFs derived from these various precursors. Muc5ac promotes the expression of CAF markers in primary AD-MSCs through STAT3 signaling. Using RNA-seq, we examined the expression of CAF subtype signatures in activated primary AD-MSCs, BM-MSCs, and PSCs. By developing a signature of activated AD-MSCs, BM-MSCs, and PSCs based on transcriptional analysis from RNA-seq and using this signature to examine the CAF population in single-cell RNA-seq, we further validated that PSCs are a minor contributor to the CAF population while AD-MSCs are a significant contributor. As epigenetic mechanisms are crucial in CAF maturation, we examined DNA methylation and histone acetylation in AD-MSCs and PSCs activated in Muc5ac-proficient and -deficient conditions. Muc5ac and its associated interactome bound to its glycan tree cause DNA methylation changes in AD-MSCs. In PSCs, Muc5ac increases histone 3 K27 acetylation independent of its associated interactome, which is also seen in a murine model. We further identified age-associated differences in CAFs as AD-MSCs isolated from young mice had increased expression of Muc5ac-induced CAF markers compared to AD-MSCs isolated from old mice. Overall, we have identified heterogeneity between CAFs derived from PSCs and AD-MSCs in terms of epigenetic maturation and subtype markers, as well as the role of Muc5ac in mediating this maturation and shaping CAF subtype.


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Available for download on Sunday, April 26, 2026