DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis.
JCI Insight
; 6(17)2021 09 08.
Article
en En
| MEDLINE
| ID: mdl-34237033
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Regulación Neoplásica de la Expresión Génica
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Carcinoma Ductal Pancreático
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Trampas Extracelulares
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Receptor con Dominio Discoidina 1
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Neoplasias Experimentales
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Neutrófilos
Límite:
Animals
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Humans
Idioma:
En
Revista:
JCI Insight
Año:
2021
Tipo del documento:
Article