DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis

Jenying Deng, Yaan Kang, Chien Chia Cheng, Xinqun Li, Bingbing Dai, Matthew H. Katz, Taoyan Men, Michael P. Kim, Eugene A. Koay, Huocong Huang, Rolf A. Brekken, Jason B. Fleming

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere146133
JournalJCI Insight
Volume6
Issue number17
DOIs
StatePublished - Sep 8 2021

ASJC Scopus subject areas

  • Medicine(all)

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