DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis
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)....
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-09-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.146133 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jenying Deng |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T15:39:35Z |
| format | Article |
| id | doaj.art-6534f5a2324842ac8f6e0b149ce8159e |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T15:39:35Z |
| publishDate | 2021-09-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-6534f5a2324842ac8f6e0b149ce8159e2022-12-22T02:41:11ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-09-01617DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasisJenying DengYaan KangChien-Chia ChengXinqun LiBingbing DaiMatthew H. KatzTaoyan MenMichael P. KimEugene A. KoayHuocong HuangRolf A. BrekkenJason B. FlemingPancreatic 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.https://doi.org/10.1172/jci.insight.146133Oncology |
| spellingShingle | 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 DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis JCI Insight Oncology |
| title | DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis |
| title_full | DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis |
| title_fullStr | DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis |
| title_full_unstemmed | DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis |
| title_short | DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis |
| title_sort | ddr1 induced neutrophil extracellular traps drive pancreatic cancer metastasis |
| topic | Oncology |
| url | https://doi.org/10.1172/jci.insight.146133 |
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