Discoidin Domain Receptor 1 (DDR1) Is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma

Jeanine M. Ruggeri, Janusz Franco-Barraza, Anjum Sohail, Yaging Zhang, Daniel Long, Marina Pasca Di Magliano, Edna Cukierman, Rafael Fridman, Howard C. Crawford

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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 languageEnglish
Pages (from-to)1735-1751
Number of pages17
JournalAmerican Journal of Pathology
Volume190
Issue number8
DOIs
StatePublished - 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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