Discoidin domain Receptor 1 (DDR1) is necessary for tissue homeostasis in pancreatic injury and pathogenesis of pancreatic ductal adenocarcinoma
Open accessAbstract
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 Kras G12D/+; Trp53 R172H/+; Ptf1a Cre/+ (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 Kras G12D/+; Ptf1a Cre/+ 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.
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Collagen acts as a signaling molecule by activating discoidin domain receptor signaling in PDAC pathology.
“Collagen also acts as a signaling molecule, activating discoidin domain receptor signaling that shape multiple roles in PDAC pathology168–171”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [168]
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- Authors
- Ruggeri, J. M., Franco-Barraza, J., Sohail, A., Zhang, Y., Long, D., Pasca di Magliano, M., Cukierman, E., Fridman, R., & Crawford, H. C.
- Affiliations
- University of Michigan (US)
- Wayne State University (US)
- Fox Chase Cancer Center (US)
- Corresponding author
- Fridman, Rafael
- Crawford, Howard C.
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 190
- Issue
- 8
- Pages
- 1735-1751
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC7416078
- OpenAlex
- W3017755151
- Cited by
- 40
- References
- 43
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 6 · 2021: 9 · 2020: 2
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Rogel Cancer Center, University of Michigan (P30CA06927)
- National Cancer Institute (P30CA06927, U01CA2241145, R50CA232985, R21CA191347)
- U.S. Department of Defense (CA170568)
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- DDR1, pancreatic ductal adenocarcinoma, chronic pancreatitis, tissue homeostasis, collagen receptor, KPC mouse model, cerulein-induced pancreatitis, pancreatic atrophy, desmoplasia, extracellular matrix remodeling, tumor progression
- MeSH terms
- Discoidin Domain Receptor 1, Animals, Homeostasis, Humans, Pancreas, Pancreatic Neoplasms, Signal Transduction, Mice, Knockout, Disease Progression, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Proliferation, Mice, Acinar Cells
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