# Identifying the pro-metastatic mechanisms of neutrophil extracellular traps

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $441,891

## Abstract

PROJECT SUMMARY
Every year, ~40,000 women in the US who had been successfully treated for primary breast cancer
nonetheless have metastatic recurrence. Metastasis requires four key steps: 1) tumor cells leave the tumor; 2)
tumor cells enter a new tissue; 3) disseminated tumor cells (DTCs) re-initiate proliferation; and 4) an
inflammatory microenvironment is established to support the growing metastasis. Steps 1-2 often happen
before the cancer is diagnosed and are rarely amenable to intervention, but we may be able to target steps 3-4
to reduce the occurrence of metastasis. To accomplish this long-term goal, we must determine a) how the
quiescent DTCs re-initiate proliferation and b) how the metastasis-supporting inflammatory microenvironment
is established. Our research on neutrophil extracellular traps (NETs) has provided novel insights into how
these processes can occur. NETs consist of meshes of genomic DNA with ~40 associated proteins, and they
are released by neutrophils to the extracellular space in response to infections and inflammation. In mouse
models, we found that lung inflammation, induced by tobacco smoke or bacterial lipopolysaccharide, triggered
quiescent DTCs to re-initiate proliferation, causing lethal metastases. Using intravital imaging, we found that
DTCs were surrounded by NETs after lung inflammation. We discovered that proteases on NETs cleave
laminin, a basement membrane protein. This cleavage generated a laminin epitope that activated integrin
receptors, triggering quiescent DTCs to proliferate. To interfere with this mechanism, we developed an
antibody against NET-cleaved laminin (ChiAb28). ChiAb28 prevented metastasis in over half of the mice and
reduced metastasis in the remaining mice. Thus, NET-associated proteases drive step 3 of the metastatic
process. In parallel, our new data show that other NET-associated proteins activate macrophages to secrete
interleukin (IL)-1β, which in turn induces more NETs and supports the metastases. This NET/macrophage
feedback loop may create an inflammatory microenvironment that supports the metastasis (step 4).
 Our data have led us to hypothesize that NETs trigger metastases from quiescent DTCs by a) cleaving
laminin to re-initiate proliferation and b) driving a feedback loop that causes local inflammation. How NETs
cleave laminin, however, is still unclear, and we will determine these mechanisms in Aim 1. How the feedback
loop between NETs and macrophages via IL-1β secretion maintain the growth of the metastasis will be
determined in Aim 2. Finally, we will combine our unique expertise in NET biology, the tumor
microenvironment, and intravital imaging to investigate combination treatments with ChiAb28 and either
chemotherapy or IL-1β blocking antibodies as new therapeutic approaches to prevent metastasis in Aim 3.
 This project will determine the mechanisms that are responsible for NETs' ability to drive the transition
from quiescent to proliferating DTCs and further to lethal m...

## Key facts

- **NIH application ID:** 11080367
- **Project number:** 5R01CA237413-06
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mikala Egeblad
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,891
- **Award type:** 5
- **Project period:** 2020-03-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11080367

## Citation

> US National Institutes of Health, RePORTER application 11080367, Identifying the pro-metastatic mechanisms of neutrophil extracellular traps (5R01CA237413-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11080367. Licensed CC0.

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