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Dissertation
The role of SCAP in pancreatic adipogenesis, pancreatitis, and pancreatic tumorigenesis
Doctor of Philosophy (Ph.D.), Drexel University
Nov 2025
DOI:
https://doi.org/10.17918/00011226
Abstract
Elevated levels of visceral fat in the digestive organs predispose individuals to pathological conditions including non-alcoholic fatty liver disease (NAFLD), cirrhosis, pancreatitis, and cancer. Studies of the signaling defects associated with these conditions have implicated deregulation of signaling by sterol regulatory element binding proteins (SREBPs) in causing the pathological features of these disorders. To evaluate the consequences of inactivating SREBP signaling in the pancreas, we analyzed a mouse model in which a Pdx1-Cre promoter inactivated SCAP, encoding a regulatory partner protein that cleaves SREBPs to support their activation, in exocrine and endocrine cells emerging from the pancreatic primordium. Although born at normal Mendelian ratios, SCAP-deficient (Scap[delta]panc) mice exhibited a rapid and progressive loss of acinar cells, and signs of acinar-ductal metaplasia. By 3 months of age, the bulk of the pancreatic mass was replaced with adipose cells, with increased fibrosis and infiltration of immune cells, indicative of pancreatitis. Lineage tracing using the Pdx1 promoter to drive expression of Td-Tomato indicated a mesenchymal source of the adipose cells. Single cell RNA sequencing (scRNAseq) confirmed loss of SCAP/SREBP transcriptional programs in endocrine and exocrine precursors, but highly elevated SREBP2 expression and signaling in SCAP-deficient mesenchymal populations. Strikingly, deletion of the SCAP knockout into the LSL-KrasG12D;Trp53f/f;Pdx1-Cre (KPC) model for pancreatic cancer significantly accelerated tumorigenesis, with a preponderance of sarcomatoid carcinomas and shortened survival. Together, these results implicate lipid metabolism via SCAP-SREBP signaling as an important metabolic regulator of acinar-ductal differentiation and pancreatic carcinogenesis.
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Details
- Title
- The role of SCAP in pancreatic adipogenesis, pancreatitis, and pancreatic tumorigenesis
- Creators
- Anna Caroline Lilly
- Contributors
- Erica Golemis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- xii, 178 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022138882404721