# Roles of neutrophils in c-Met mediated breast cancer brain metastases

> **NIH NIH R37** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $354,563

## Abstract

The majority of cancer death is attributed to metastatic disease, and the brain is one of the major sites of
breast tumor metastasis. Even with the advanced treatment such as stereotactic radiosurgery (SRS), the
median survival of breast cancer patients who developed brain metastases is less than a year. Regardless of
high clinical significance, the pathological mechanism of brain metastasis is still poorly understood. We
recently found that (i) c-Met signaling is able to induce the expression of a group of inflammatory genes which
play critical roles in the generation of N2 neutrophils in the brain metastatic lesions, (ii) N2 neutrophils promote
the self-renewal of cancer stem-like cells and suppress T cell mediated immune surveillance and (iii) the BBB
permeable natural compound, PTER, suppresses brain metastasis by selectively targeting the c-Met. These
novel and discoveries led us to hypothesize that (i) c-Met promotes brain metastasis and resistance to the
radiation therapy by generating N2 neutrophils, and (ii) N2 neutrophils in turn enhance self-renewal of cancer
stem-like cells and promote local immune suppression. We also hypothesize that pterostilbene (PTER), a BBB
permeable natural compound suppresses brain metastasis and relapse after radio-therapy by suppressing c-
Met signaling and thereby reducing the amount of N2 neutrophils. To test these hypotheses, we will (i)
investigate how c-Met-induced neutrophil regulatory factors (NRFs) modulate neutrophil activities in the brain
metastatic lesions (Aim1), (ii) decipher the mechanisms by which N2 neutrophils promote tumor progression
and radio-resistance (Aim 2), and (iii) test the efficacy of PTER in suppressing BrM and post-SRS recurrence
in vivo (Aim 3). The project is highly innovative. First, we have established a state-of-the-art system biology
screening approach and found that overexpression of c-Met is strongly correlated with patients who developed
brain metastasis and it is associated with an induction of NRFs which promotes phenotypic changes of
neutrophils in metastatic sites. Therefore, the outcome of this project will reveal novel pathological
mechanisms of how neutrophil modulation by cancer-secreted factors contributes to the brain metastasis.
Secondly, the exact feed-back mechanism by which N2 neutrophils promote tumor progression and radio-
resistance is poorly understood. We propose to decipher the pathway of reciprocal interaction between tumor
cells, N2 neutrophils and T-cells in the brain microenvironment, which we believe will lead to a discovery of
novel therapeutic approaches to target N2 neutrophils. Finally, we will examine the potential utility of the BBB-
permeable natural compound, PTER, as a therapeutic agent and a radiosensitizer agent for treating brain
metastasis. If our hypotheses are borne out, this work has the potential to be a novel paradigm that could
significantly improve the treatment and prevention of breast cancer.

## Key facts

- **NIH application ID:** 9989087
- **Project number:** 5R37CA230451-03
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Fei Xing
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,563
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989087

## Citation

> US National Institutes of Health, RePORTER application 9989087, Roles of neutrophils in c-Met mediated breast cancer brain metastases (5R37CA230451-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989087. Licensed CC0.

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