Abstract
Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis are characterized by a dense collagen-rich desmoplastic reaction. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagens that can regulate cell proliferation, migration, adhesion, and remodeling of the extracellular matrix. To address the role of DDR1 in PDA, Ddr1-null (Ddr−/−) mice were crossed with the KrasG12D/+; Trp53R172H/+; Ptf1aCre/+ (KPC) model of metastatic PDA. Ddr1−/−; KPC mice progress to differentiated PDA but resist progression to poorly differentiated cancer compared with KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in Ddr1−/−; KPC mice. To further explore the effects of Ddr1 ablation, Ddr1−/− mice were crossed with the KrasG12D/+; Ptf1aCre/+ neoplasia model and subjected to cerulein-induced experimental pancreatitis. Similar to KPC mice, tissue atrophy was a hallmark of both neoplasia and pancreatitis models in the absence of Ddr1. Compared with controls, Ddr1−/− models had increased acinar cell dropout and reduced proliferation with no difference in apoptotic cell death between control and Ddr1−/− animals. In most models, organ atrophy was accompanied by increased fibrillar collagen deposition, suggesting a compensatory response in the absence of this collagen receptor. Overall, these data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.
Original language | English |
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Pages (from-to) | 1735-1751 |
Number of pages | 17 |
Journal | American Journal of Pathology |
Volume | 190 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2020 |
Keywords
- Acinar Cells/metabolism
- Animals
- Carcinoma, Pancreatic Ductal/genetics
- Cell Line, Tumor
- Cell Proliferation/physiology
- Discoidin Domain Receptor 1/genetics
- Disease Progression
- Homeostasis/physiology
- Humans
- Mice
- Mice, Knockout
- Pancreas/metabolism
- Pancreatic Neoplasms/genetics
- Signal Transduction/physiology
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