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Ruggeri JM, Franco-Barraza J, Sohail A, Zhang Y, Long D, Pasca di Magliano M, Cukierman E, Fridman R, Crawford HC
Discoidin Domain Receptor 1 (DDR1) is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma
Am J Pathol (2020) In process.
Abstract
Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis (CP) 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 (ECM). To address the role of DDR1 in PDA, we crossed DDR1-null (DDR1(-/-)) mice into the Kras(G12D/+); Trp53(R172H/+); Ptf1a(Cre/+)(KPC) model of metastatic PDA. We found that DDR1(-/-); KPC mice progress to differentiated PDA, but resist progression to poorly-differentiated cancer, compared to KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in DDR1(-/-); KPC mice. To further explore the effects of DDR1 ablation, we crossed the DDR1(-/-) mice into the Kras(G12D/+); Ptf1a(Cre/+)(KC) neoplasia model and also subjected them 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 to controls, DDR1(-/-) models showed increased acinar cell drop-out 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, our data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.
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Publication Date: 2020-04-24.
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Last updated on Thursday, June 04, 2020