1. Discoidin Domain Receptor 1 (DDR1) Is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma
- Author
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Anjum Sohail, Yaqing Zhang, Daniel Long, Jeanine M. Ruggeri, Janusz Franco-Barraza, Marina Pasca di Magliano, Rafael Fridman, Edna Cukierman, and Howard C. Crawford
- Subjects
0301 basic medicine ,Acinar Cells ,Article ,Pathology and Forensic Medicine ,Collagen receptor ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Discoidin Domain Receptor 1 ,Cell Line, Tumor ,medicine ,Acinar cell ,Animals ,Homeostasis ,Humans ,Pancreas ,Tissue homeostasis ,Cell Proliferation ,Mice, Knockout ,DDR1 ,Chemistry ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Pancreatitis ,Discoidin domain ,Carcinoma, Pancreatic Ductal ,Signal Transduction - 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.
- Published
- 2020