Neutrophil extracellular trap gene expression signatures identify prognostic and targetable signaling axes for inhibiting pancreatic tumour metastasis

Paul C McDonald ¹, James T Topham ², Shannon Awrey ¹

¹Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, BC, Canada.
²Pancreas Centre BC, Vancouver General Hospital, Vancouver, BC, Canada.
³Aspect Biosystems, Vancouver, BC, Canada.
⁴adMare BioInnovations, Vancouver, BC, Canada.
⁵Departments of Surgery and Oncology, Cummings School of Medicine, University of Calgary, Calgary, AB, Canada.
⁶Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
⁷Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.
⁸Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
⁹Medical Oncology, BC Cancer, Vancouver, BC, Canada.
¹⁰Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹¹Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, BC, Canada. sdedhar@bccrc.ca.
¹²Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada. sdedhar@bccrc.ca.

⁰Department of Basic and Translational Research, BC Cancer Research Institute, Vancouver, BC, Canada.

Communications Biology +

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July 4, 2025

View abstract on PubMed

Summary

Neutrophil Extracellular Traps (NETs) drive pancreatic cancer metastasis by activating signaling pathways. Targeting these pathways, like ILK, can inhibit cancer progression and improve patient outcomes.

Area Of Science

Oncology
Immunology
Molecular Biology

Background

Tumor-associated neutrophils (TANs) and Neutrophil Extracellular Traps (NETs) are implicated in cancer metastasis.
The specific molecular mechanisms of NET interaction with Pancreatic Ductal Adenocarcinoma (PDAC) cells are not well understood.

Purpose Of The Study

To investigate the role of NETs in PDAC progression and metastasis.
To identify novel gene expression signatures and signaling pathways for PDAC patient stratification and therapeutic targeting.

Main Methods

Consensus clustering and pathway enrichment analysis of NET-related genes in 369 PDAC patient samples.
Analysis of tumor-infiltrating neutrophils and NETs association with specific proteins (ITGB1, CCDC25, ILK) in PDAC.
Experimental metastasis models in mice (NOD scid gamma) to assess the impact of ILK knockdown on NETosis-driven metastasis.

Main Results

Two gene expression signatures associated with patient survival were identified: one linked to integrin-actin cytoskeleton and Epithelial to Mesenchymal Transition (EMT) signaling, and another to cell death signaling.
NETs promote PDAC cell EMT, migration, and invasion through a CCDC25-ITGB1-ILK signaling complex.
ILK knockdown significantly inhibited NETosis-driven experimental lung metastasis of PDAC cells.

Conclusions

Novel NET-related gene expression signatures can aid in PDAC patient stratification.
The identified NET-driven signaling axis (CCDC25-ITGB1-ILK) represents a potential therapeutic target to prevent and treat PDAC progression and metastasis.