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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 Aug;190(8) :1735-1751
PMID: 32339496    PMCID: PMC7416078    URL: https://www.ncbi.nlm.nih.gov/pubmed/32339496
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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 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.
Notes
1525-2191 Ruggeri, Jeanine M Franco-Barraza, Janusz Sohail, Anjum Zhang, Yaqing Long, Daniel Pasca di Magliano, Marina Cukierman, Edna Fridman, Rafael Crawford, Howard C R21 CA231252/CA/NCI NIH HHS/United States P30 CA046592/CA/NCI NIH HHS/United States R01 CA232256/CA/NCI NIH HHS/United States R21 CA191347/CA/NCI NIH HHS/United States R50 CA232985/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Pathol. 2020 Aug;190(8):1735-1751. doi: 10.1016/j.ajpath.2020.03.020. Epub 2020 Apr 24.