Journal article
Role of SCAP in regulation of pancreatic homeostasis, pancreatitis, and tumorigenesis
Oncogene
15 Apr 2026
PMID: 41986652
Featured in Collection : Drexel's Newest Publications
Abstract
Levels of pancreatic ductal adenocarcinoma (PDAC) are increasing, with epidemiological studies nominating obesity, altered cholesterol metabolism, and elevated lipids as risk factors. In prior studies, we determined that elevated expression of sterol regulatory element binding protein 2 (SREBP2), a transcription factor directing lipid biosynthesis, promoted epithelial-mesenchymal transition and aggressive tumorigenesis in the KPC (LSL-KrasG12D;Trp53f/f;Pdx1-Cre) mouse model of PDAC. We analyzed the consequences of deleting SCAP, a scaffolding protein required for SREBP activation, in KPC mice. Unexpectedly tumorigenesis in KPCS mice was significantly accelerated, with a preponderance of sarcomatoid carcinomas. To better understand SCAP action, we analyzed loss of pancreatic SCAP in isolation in ScapΔpanc (Pdx1-Cre;Scapf/f) mice. Pancreata of ScapΔpanc mice had rapid progressive loss of acinar cells, acinar-ductal metaplasia (ADM), infiltration of adipose cells, increased fibrosis, and infiltration of immune cells, indicative of chronic pancreatitis. Single cell RNA sequencing indicated that loss of SCAP suppressed SREBP-dependent transcriptional programs in endocrine and exocrine precursors, but was associated with enhanced SREBP2 activity in fibroblastic populations, compatible with formation of a pro-tumorigenic tumor microenvironment. 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
- Role of SCAP in regulation of pancreatic homeostasis, pancreatitis, and tumorigenesis
- Creators
- Anna C Lilly - Drexel University, College of MedicineValerii A Pavlov - Cincinnati Children's Hospital Medical CenterShabnam Pirestani - Molecular & Cell Biology & Genetics (MCBG) Program, Drexel University College of Medicine, Philadelphia, PA, USAAdam Chatoff - Temple UniversityKathy Q Cai - Fox Chase Cancer CenterEdna Cukierman - Drexel University, Graduate School of Biomedical Sciences and Professional StudiesNathaniel W Snyder - Drexel University, A.J. Drexel Autism InstituteIgor Astsaturov - Fox Chase Cancer CenterErica A Golemis - Drexel University, Biochemistry and Molecular Biology
- Publication Details
- Oncogene
- Grant note
- CA06927 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA269660 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA298386 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Graduate School of Biomedical Sciences and Professional Studies; School of Biomedical Engineering, Science, and Health Systems; A.J. Drexel Autism Institute
- Web of Science ID
- WOS:001740853400001
- Scopus ID
- 2-s2.0-105035774271
- Other Identifier
- 991022180002604721