Date of Award
Spring 4-25-2025
Document Type
Thesis (Ph.D.)
Department or Program
Molecular and Systems Biology
First Advisor
Steven D. Leach
Abstract
While the majority of human pancreatic cancers are classified as ductal adenocarcinomas, the cell of origin of these tumors remains uncertain and many tumors are comprised of dedifferentiated cell types, making it imperative to understand the full spectrum of neoplastic differentiation and how it is regulated. The central focus of this dissertation is the utilization of a zebrafish model of pancreatic cancer driven by tissuespecific expression of UAS:mKO2-KRASG12D under the regulation of a Ptf1a:Gal4-VP16 transcriptional driver to elucidate mechanisms of tumorigenesis and differentiation. Transgenic zebrafish generate heterogenous tumors comprised histologically of mixed acinar and ductal elements, providing the opportunity to interrogate specific transcriptional and epigenetic modifiers responsible for regulating neoplastic pancreatic cellular differentiation. Single-cell RNA sequencing of these tumors has confirmed neoplastic cell populations expressing exclusively acinar and ductal markers, as well as distinct clusters expressing markers of both cell lineages and additional progenitor-like cells. Screening a panel of 21 unique chromatin modifiers and chromatin readers for differential expression in these distinct cell clusters reveals hdac9b to be upregulated in the progenitor-like population enriched for ductal features [1]. Pseudo-time trajectory inferences support an acinar cell-of-origin for these hdac9b-expressing progenitor-like cells. Treatment of fish with the class IIA HDAC inhibitor TMP195 supports a functional role of HDAC activity in regulating neoplastic cell differentiation through activation of pancreatic progenitor gene expression and repression of the acinar cell state (Graphical Abstract). This work further shows that neoplastic gene signatures from zebrafish are conserved in premalignancy and progenitor-like populations in murine tissue and have a high correlation with human transcriptional subtype signatures. The human ortholog, HDAC9, is a strong predictor of overall survival in PDAC patients with classical tumors. These findings are described in detail in Chapter 2 and may lead to new strategies for therapeutic manipulation of neoplastic cell differentiation. Additional methods and attempts at pancreatic cancer modeling in zebrafish are outlined in Chapter 3.
Recommended Citation
Matar, Somer Mary, "Single-Cell Transcriptomics Reveal the Heterogeneous Landscape of Epithelial Identity During Zebrafish Pancreatic Tumorigenesis" (2025). Dartmouth College Ph.D Dissertations. 346.
https://digitalcommons.dartmouth.edu/dissertations/346
