# Nicotine promotes perineural brain metastasis by activating GABAergic neurons

> **NIH NIH K99** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $109,014

## Abstract

PROJECT SUMMARY/ABSTRACT
Patients with brain metastasis of lung cancer have extremely poor prognosis, high mortality rate, and frequent
incidence of tumor recurrence. Understanding the pathological mechanism of brain metastasis is urgently
needed to develop a novel and effective therapeutic strategy. Published data as well as the results of my own
study for brain metastasis of lung cancer indicate that smoking and nicotine significantly increased the
incidence and progression of brain metastasis, but the pathological mechanism by which the smoking
promotes brain metastasis through modulating brain microenvironment is yet poorly understood. Our
preliminary results showed that synaptic formation in brain metastasis region is strongly correlated with poor
overall survival of patients with brain metastasis. However, the exact role of neurons in brain metastasis
progression remains unclear. The goal of this proposal is to elucidate the mechanism of GABAnergic neuron
activation in the brain metastasis in order to develop innovative strategies for the treatment of brain metastasis.
I hypothesize that nicotine stimulates microglia to secrete exosomal miR-32-3p which promotes brain
metastasis by augmenting GABAergic synaptic formation and hence releasing GABA that serves as metabolic
substrate to fuel tumor cell growth. I also hypothesize that inhibiting the GABA transporter of tumor cell
suppresses brain metastasis by blocking GABA shunt. In Aim 1, I will clarify the molecular pathway through
which nicotine stimulates microglia to secrete exosomal miR32-3p and activates GABAergic neuron. In Aim 2,
I will investigate the pathological mechanism by which the activated GABAergic neuron enhances brain
metastasis by promoting GABA shunt of tumor cells. Aim 3 is to test the efficacy of inhibitors for GABA
transporter on nicotine-stimulated brain metastasis.
The K99 phase of the proposed research will be pursued at Wake Forest University (WFU), an interactive
cancer biology community, and a wealth of intellectual and technical resources. The training plan, under the
mentorship of Dr. Watabe, outlines a comprehensive strategy for acquiring the technical and the professional
skills required to complete the proposed research and prepare me for an independent research career.
Experienced six members of my mentor team will provide training in new techniques and analyses of data. By
taking advantage of Wake Forest‘s exceptional resources for professional development, I will also improve my
skills for communication, management, and leadership. The training I obtain at WFU will equip me to lead a
laboratory that merges diverse approaches to investigate the mechanisms of initiation and progression to
clinically significant brain metastasis and identify innovative strategies for prevention and treatment of brain
metastasis.

## Key facts

- **NIH application ID:** 10814887
- **Project number:** 5K99CA276895-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Shih-Ying Wu
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $109,014
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814887

## Citation

> US National Institutes of Health, RePORTER application 10814887, Nicotine promotes perineural brain metastasis by activating GABAergic neurons (5K99CA276895-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10814887. Licensed CC0.

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