DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis

JCI Insight. 2021 Sep 8;6(17):e146133. doi: 10.1172/jci.insight.146133.


Pancreatic ductal adenocarcinoma (PDAC) tumors are characterized by a desmoplastic reaction resulting in dense deposition of collagen that is known to promote cancer progression. A central mediator of protumorigenic collagen signaling is the receptor tyrosine kinase discoid domain receptor 1 (DDR1). DDR1 is a critical driver of a mesenchymal and invasive cancer cell PDAC phenotype. Previous studies have demonstrated that genetic or pharmacologic inhibition of DDR1 reduces PDAC tumorigenesis and metastasis. Here, we investigated whether DDR1 signaling has cancer cell nonautonomous effects that promote PDAC progression and metastasis. We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. Moreover, we have identified that collagen-induced CXCL5 production was mediated by a DDR1/PKCθ/SYK/NF-κB signaling cascade. Together, these results highlight the critical contribution of the collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis.

Keywords: Cytokines; Neutrophils; Oncology; Signal transduction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinogenesis
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / secondary
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • DNA, Neoplasm / genetics
  • Discoidin Domain Receptor 1 / biosynthesis
  • Discoidin Domain Receptor 1 / genetics*
  • Extracellular Traps / genetics*
  • Extracellular Traps / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplasms, Experimental*
  • Neutrophils / metabolism
  • Neutrophils / pathology*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Signal Transduction
  • Tumor Microenvironment


  • DNA, Neoplasm
  • Ddr1 protein, mouse
  • Discoidin Domain Receptor 1