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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States
Recent evidence demonstrates that the genetic ablation of discoid domain receptor 1 (DDR1) in a genetically engineered mouse model (GEMM) of PDAC resulted in a significant reduction of metastasis [11]
We report a potentially novel mechanism by which a collagen receptor, DDR1, on PDAC cells interacts with type I collagen to attract tumor-associated neutrophils, induce neutrophil extracellular traps (NETs) formation, and facilitate cancer cell invasion and metastasis
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. One of the major ECM components is collagen, which can promote cancer cell survival and facilitate invasion [4, 5]. DDRs have been shown to regulate cancer cell survival, adhesion, proliferation, motility, and invasion in different settings [7]. Collagen-DDR1 signaling can induce an invasive phenotype in pancreatic cancer cells through an epithelial-mesenchymal transition (EMT) [9, 10]. DDR1 might be a critical mediator of collagen-driven tumorigenesis in PDAC. We reported in an earlier study that the pharmacological inhibition of DDR1 activation by a novel small-molecule inhibitor, 7rh benzamide, inhibited tumorigenesis and enhanced chemosensitivity in orthotopic xenografts and autochthonous pancreatic tumors [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
