Ddr1-induced neutrophil extracellular traps drive pancreatic cancer metastasis

Pancreatic ductal adenocarcinoma (PDAC) tumors are characterized by a desmoplastic reaction and dense collagen that is known to promote cancer progression. A central mediator of pro-tumorigenic 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 prevents PDAC tumorigenesis and metastasis. Here, we investigated whether DDR1 signaling has cancer cell non-autonomous 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-NFκB signaling cascade. Together, these results highlight the critical contribution of collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis. Summary Deng et al find that collagen signaling via DDR1 on human pancreatic cancer cells drives production and release of the cytokine, CXCL5, into systemic circulation. CXCL5 then triggers infiltration of neutrophils into the tumor where they promote cancer cell progression. ### Competing Interest Statement The authors have declared no competing interest. * CCM : cancer cell conditioned medium ChIP : chromatin immunoprecipitation NCCM : cancer cell neutrophil conditioned medium DDR : discoid domain receptor ECM : extracellular matrix EMT : epithelial-mesenchymal transition ENA-78 : epithelial-derived neutrophil-activating peptid 78 GAPDH : glyceraldehyde 3-phosphate dehydrogenase GEMM : genetically engineered mouse model MPO : myeloperoxidase NADPH : nicotinamide adenine dinucleotide phosphate NCCM : neutrophils exposed to cancer cell conditioned media NCM : neutrophil conditioned medium NE : neutrophil elastase NETs : neutrophil extracellular traps PAD4 : peptidylarginine 4 PDAC : pancreatic ductal adenocarcinoma PDX : patient-derived xenograft PMA : phorbol myristate acetate TAMs : tumor-associated macrophages TANs : tumor-associated neutrophils TME : tumor microenvironment