Type
Text
Type
Dissertation
Advisor
Furie, Martha | Crawford, Howard C | Zong, Wei-Xing | van der Velden, Adrianus | Egeblad, Mikala
Date
2012-12-01
Keywords
Cellular biology--Biology--Microbiology | EGFR, lipopolysaccharide, pancreatic cancer, Salmonella, Sox17, Tuft cells
Department
Department of Molecular Genetics and Microbiology
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/71200
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease due to lack of early detection, making the study of initiating events, intrinsic and extrinsic, invaluable. An aberrant epithelial structure consistently associated with PDAC development is the metaplastic ductal lesion (MDL), formed as a result of acinar to ductal metaplasia (ADM) and hypothesized to be pre-neoplastic. Through lineage tracing and immunohistochemistry I have determined that MDLs derive from acinar cells that have converted to structures resembling the developmentally related biliary duct gland. Consistent with this process, MDLs co-express the transcription factors PDX1 and SOX17, a molecular signature reserved for pancreatobiliary progenitor cells during organ development. Additionally, I have found that tuft cells (TCs) are consistently associated with MDLs, a characteristic of the normal bile duct. To probe the importance of pancreas-to-biliary metaplasia, I utilized a transgenic SOX17 overexpression murine model. I found that SOX17 overexpression is sufficient to drive a metaplastic, pancreatitis-like disease state, complete with TC transdifferentiation. While genetic mutation is sufficient to induce pancreatitis, a risk factor for PDAC, extrinsic factors are considered more common effectors. In attempt to discern what environmental stimuli are sufficient to induce pancreatitis, I utilized models of Salmonella enterica serovar Typhimurium infection and found that infection is sufficient to induce pancreatitis, including ADM, a possible source of neoplasia. Simulation of infection through lipopolysaccharide-treatment of genetically engineered mouse models suggests that infection is pro-tumorigenic and requires epidermal growth factor receptor (EGFR). My analysis of ADM reveals that both cell intrinsic programming and extrinsic environmental stimuli are sufficient to induce both inflammation and ADM, considered early events in PDAC development. | 125 pages
Recommended Citation
DelGiorno, Kathleen Elizabeth, "Causes and effects of epithelial morphogenesis in pancreatitis and pancreatic cancer" (2012). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 406.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/406