# Circulating tumor cell-neutrophil clusters in breast cancer metastasis

> **NIH NIH P20** · UNIVERSITY OF KENTUCKY · 2022 · $351,430

## Abstract

PROJECT SUMMARY
Metastasis causes a majority of breast cancer (BCa)-related deaths. Among all types of BCas, triple-negative
breast cancers (TNBCs) are more aggressive and have a poorer prognosis. To metastasize, cancer cells must
enter into the circulatory system. These circulating tumor cells (CTCs) are considered the seeds of metastasis.
Recently, both our preliminary data and other studies have shown that neutrophils can interact with a
subpopulation of CTCs (named CTC-neutrophil clusters) to facilitate metastasis. However, the features of
neutrophil-associated CTCs, and how CTC-associated neutrophils facilitate metastasis has yet to be determined.
The overall objective of this proposal is to identify and characterize neutrophil-associated CTCs, and how the
interaction promotes metastasis, with the hope of developing a novel therapeutic strategy to inhibit metastasis
by blocking CTC-neutrophil cluster formation. We found that the intercellular adhesion molecule 1 (ICAM-1),
which is well-known to bind to Mac-1 on neutrophils, is overexpressed in lung metastases, and knockdown of
ICAM-1 inhibits TNBC metastasis. In addition, ICAM-1+ TNBC cells produce high level of soluble urokinase
plasminogen activator receptor (uPAR). Since uPAR is a potent chemoattractant for recruitment of neutrophils,
and facilitates Mac-1-mediated adhesion, we hypothesize that ICAM-1+ CTCs are prone to associate with
neutrophil by increasing suPAR production to enhance their metastatic ability. Furthermore, our preliminary
findings indicate that Mac-1 expression is upregulated in circulating neutrophils from tumor-bearing mice. Since
both phospholipase A2 and arachidonate 5-lipoxygenase, the key enzymes in arachidonic acid (AA) metabolism,
can upregulate Mac-1 expression, we also hypothesize that enhanced AA metabolism in circulating neutrophils
is required for their interaction with CTCs to promote metastasis. We propose 2 Specific Aims: 1) to determine
the molecular mechanisms by which ICAM-1 promotes BCa metastasis, particularly whether uPAR facilitates
ICAM-1 and Mac-1 mediated CTC and neutrophil interaction using both mouse and human TNBC models; 2) to
dissect the role of AA metabolism in the pro-metastatic activity of circulating neutrophils using blood samples
from both TNBC mouse models and BCa patients. The results from this proposal will not only reveal new
mechanisms of metastasis, but also have significant implications for understanding how AA metabolism
regulates pro-metastatic function of neutrophils, which will pave the way for the design of next-generation
neutrophil-based immunotherapy.

## Key facts

- **NIH application ID:** 10271868
- **Project number:** 2P20GM121327-06
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Xia x Liu
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,430
- **Award type:** 2
- **Project period:** 2017-03-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271868

## Citation

> US National Institutes of Health, RePORTER application 10271868, Circulating tumor cell-neutrophil clusters in breast cancer metastasis (2P20GM121327-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10271868. Licensed CC0.

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