ORCID ID
Graduation Date
Spring 5-4-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Interdisciplinary Graduate Program in Biomedical Sciences
First Advisor
Dr. Sushil Kumar
Abstract
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.
Recommended Citation
Kehrberg, Rachel J., "Mucin 5ac Modulates Cancer-Associated Fibroblast Heterogeneity through Epigenetic Regulation" (2024). Theses & Dissertations. 840.
https://digitalcommons.unmc.edu/etd/840
Comments
2024 Copyright, the authors