Neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis
Abstract Tumour associated neutrophils (TANs) promote metastasis through interactions of Neutrophil Extracellular Traps (NETs) with tumour cells. However, molecular details surrounding the interactions between NETs and Pancreatic Ductal Adenocarcinoma (PDAC) cells are poorly understood. Here, we exa...
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| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08440-x |
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| author | Paul C. McDonald James T. Topham Shannon Awrey Hossein Tavakoli Rebekah Carroll Wells S. Brown Zachary J. Gerbec Steve E. Kalloger Joanna M. Karasinska Patricia Tang Rachel Goodwin Steven J. M. Jones Janessa Laskin Marco A. Marra Gregg B. Morin Daniel J. Renouf David F. Schaeffer Shoukat Dedhar |
| author_facet | Paul C. McDonald James T. Topham Shannon Awrey Hossein Tavakoli Rebekah Carroll Wells S. Brown Zachary J. Gerbec Steve E. Kalloger Joanna M. Karasinska Patricia Tang Rachel Goodwin Steven J. M. Jones Janessa Laskin Marco A. Marra Gregg B. Morin Daniel J. Renouf David F. Schaeffer Shoukat Dedhar |
| author_sort | Paul C. McDonald |
| collection | DOAJ |
| description | Abstract Tumour associated neutrophils (TANs) promote metastasis through interactions of Neutrophil Extracellular Traps (NETs) with tumour cells. However, molecular details surrounding the interactions between NETs and Pancreatic Ductal Adenocarcinoma (PDAC) cells are poorly understood. Here, we examine the contribution of NETs in the progression of PDAC, which is characterized by high metastatic propensity. We carry out consensus clustering and pathway enrichment analysis of NET-related genes in an integrated cohort of 369 resectable and metastatic PDAC patient tumour samples, and compile two gene expression signatures comprising of either, integrin-actin cytoskeleton and Epithelial to Mesenchymal Transition (EMT) signaling, or cell death signaling, which identifies patients with very poor to better overall survival, respectively. Tumour Infiltrating neutrophils and NETs associate with ITGB1, CCDC25 and ILK, within clinical and experimental PDAC tumours. Functionally, exposure of PDAC cells to NETs identifies a cytoskeletal dynamic-associated CCDC25-ITGB1-ILK signaling complex which stimulates EMT and migration/invasion. NETosis-driven experimental metastasis to the lungs of PDAC cells delivered through the tail vein of female non-obese diabetic (NOD) scid gamma (NSG) mice is significantly inhibited by ILK knock down. Our data identify novel NET-related gene expression signatures for PDAC patient stratification, and reveal targetable signaling axes to prevent and treat disease progression. |
| format | Article |
| id | doaj-art-639b337ebb87452ea119c00a3cc5d3dc |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-639b337ebb87452ea119c00a3cc5d3dc2025-08-20T03:03:45ZengNature PortfolioCommunications Biology2399-36422025-07-018111910.1038/s42003-025-08440-xNeutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasisPaul C. McDonald0James T. Topham1Shannon Awrey2Hossein Tavakoli3Rebekah Carroll4Wells S. Brown5Zachary J. Gerbec6Steve E. Kalloger7Joanna M. Karasinska8Patricia Tang9Rachel Goodwin10Steven J. M. Jones11Janessa Laskin12Marco A. Marra13Gregg B. Morin14Daniel J. Renouf15David F. Schaeffer16Shoukat Dedhar17Department of Basic and Translational Research, BC Cancer Research InstitutePancreas Centre BC, Vancouver General HospitalDepartment of Basic and Translational Research, BC Cancer Research InstituteDepartment of Basic and Translational Research, BC Cancer Research InstituteDepartment of Basic and Translational Research, BC Cancer Research InstituteDepartment of Basic and Translational Research, BC Cancer Research InstituteDepartment of Basic and Translational Research, BC Cancer Research InstitutePancreas Centre BC, Vancouver General HospitalPancreas Centre BC, Vancouver General HospitalDepartments of Surgery and Oncology, Cummings School of Medicine, University of CalgaryOttawa Hospital Cancer Centre, Ottawa Hospital Research InstituteCanada’s Michael Smith Genome Sciences Centre, BC CancerCanada’s Michael Smith Genome Sciences Centre, BC CancerCanada’s Michael Smith Genome Sciences Centre, BC CancerCanada’s Michael Smith Genome Sciences Centre, BC CancerPancreas Centre BC, Vancouver General HospitalPancreas Centre BC, Vancouver General HospitalDepartment of Basic and Translational Research, BC Cancer Research InstituteAbstract Tumour associated neutrophils (TANs) promote metastasis through interactions of Neutrophil Extracellular Traps (NETs) with tumour cells. However, molecular details surrounding the interactions between NETs and Pancreatic Ductal Adenocarcinoma (PDAC) cells are poorly understood. Here, we examine the contribution of NETs in the progression of PDAC, which is characterized by high metastatic propensity. We carry out consensus clustering and pathway enrichment analysis of NET-related genes in an integrated cohort of 369 resectable and metastatic PDAC patient tumour samples, and compile two gene expression signatures comprising of either, integrin-actin cytoskeleton and Epithelial to Mesenchymal Transition (EMT) signaling, or cell death signaling, which identifies patients with very poor to better overall survival, respectively. Tumour Infiltrating neutrophils and NETs associate with ITGB1, CCDC25 and ILK, within clinical and experimental PDAC tumours. Functionally, exposure of PDAC cells to NETs identifies a cytoskeletal dynamic-associated CCDC25-ITGB1-ILK signaling complex which stimulates EMT and migration/invasion. NETosis-driven experimental metastasis to the lungs of PDAC cells delivered through the tail vein of female non-obese diabetic (NOD) scid gamma (NSG) mice is significantly inhibited by ILK knock down. Our data identify novel NET-related gene expression signatures for PDAC patient stratification, and reveal targetable signaling axes to prevent and treat disease progression.https://doi.org/10.1038/s42003-025-08440-x |
| spellingShingle | Paul C. McDonald James T. Topham Shannon Awrey Hossein Tavakoli Rebekah Carroll Wells S. Brown Zachary J. Gerbec Steve E. Kalloger Joanna M. Karasinska Patricia Tang Rachel Goodwin Steven J. M. Jones Janessa Laskin Marco A. Marra Gregg B. Morin Daniel J. Renouf David F. Schaeffer Shoukat Dedhar Neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis Communications Biology |
| title | Neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis |
| title_full | Neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis |
| title_fullStr | Neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis |
| title_full_unstemmed | Neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis |
| title_short | Neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis |
| title_sort | neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis |
| url | https://doi.org/10.1038/s42003-025-08440-x |
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