# Role of Neutrophil Extracellular Traps in Pancreatic Cancer

> **NIH NIH P20** · WEST VIRGINIA UNIVERSITY · 2024 · $259,037

## Abstract

PROJECT SUMMARY/ABSTRACT – Role of Neutrophil Extracellular Traps in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by a fibrotic and
immunosuppressive tumor microenvironment that promotes resistance to therapy. Innovative approaches to
overcome the pathophysiology in the PDAC tumor microenvironment (TME) that drive treatment resistance are
desperately needed. The uniquely fibrotic TME serves as a physical barrier to prevent infiltration of T cells and
has limited functional vasculature, which reduces the delivery of chemotherapy. We have recently
demonstrated that neutrophil extracellular traps (NETs), in which activated neutrophils release their
intracellular contents including DNA, histones and granules into the extracellular space or circulation, are
upregulated in pancreatic cancer, driving tumor growth and promoting fibrosis through pancreatic stellate cell
(PSC) activation. Protein arginine deiminase 4 (PAD4) is an enzyme that citrullinates histones to allow for
unwinding and expulsion from the cell and is required for NET formation, providing a potential therapeutic
target for NET inhibition in cancer. PAD4-/- mice have diminished local and systemic NET formation, resulting in
limited tumor growth and improved survival in murine orthotopic pancreatic cancer. We have generated
preliminary data demonstrating that PDAC mice with genetic ablation of PAD4 have enhanced cytotoxic
immune response and increased functional vasculature. The objective of this application is to identify the
impactful mechanisms through which NETs promote treatment resistance to immunotherapy and
chemotherapy. We will explore the impact of PAD4 ablation on spontaneous transgenic Kras and p53
mediated PDAC. In Aim 1, we will thoroughly evaluate the immune response to PAD4 ablation/inhibition with a
focus on how reduction in PSC activation as a result of diminished NETs enhances T cell infiltration and
function, promoting response to immunotherapy. In Aim 2, we will evaluate the changes that NETs have on
angiogenesis, functional vasculature and delivery of cytotoxic chemotherapy. These studies will support
translation of novel therapeutic approaches in combination with standard of care chemotherapy and
immunotherapy to maximize treatment response in this devastating disease.

## Key facts

- **NIH application ID:** 10916366
- **Project number:** 5P20GM121322-07
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** BRIAN A BOONE
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $259,037
- **Award type:** 5
- **Project period:** 2018-08-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916366

## Citation

> US National Institutes of Health, RePORTER application 10916366, Role of Neutrophil Extracellular Traps in Pancreatic Cancer (5P20GM121322-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10916366. Licensed CC0.

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