# Investigating the role of glutamine metabolism in breast tumor innervation and brain metastasis

> **NIH NIH P20** · UNIVERSITY OF ARKANSAS AT FAYETTEVILLE · 2023 · $216,294

## Abstract

Project Summary – Project Leader Young Hye Song
The overall goal of this project is to understand the role of altered glutamine metabolism in breast tumor
innervation and its connection to brain metastasis. Recent analyses of clinical data have shown that nerve fibers
are significantly more present in invasive ductal carcinoma compared to both ductal carcinoma in situ and normal
breast tissue. There exists evidence that glutamine metabolism may promote breast tumor innervation and brain
metastasis: 1) breast cancer cells express high levels of glutaminase that initiates glutaminolysis by converting
glutamine to glutamate, 2) cancer-associated fibroblasts upregulate glutamine synthetase expression to meet
glutamine demands of breast cancer cells, 3) a synergy between glycolysis and glutaminolysis enhances cancer
cell conversion of glutamine to lactate, which stimulates brain-derived neurotrophic factor (BDNF) secretion and
drive neurite extension, 4) brain metastasizing breast cancer cells express post-synaptic marker PSD-95 and
BDNF receptor TrkB. Yet, the potential to inhibit these several key metabolic pathways and reduce metastatic
phenotypes in triple negative breast cancer have not been clearly elucidated. To this end, we hypothesize that
elevated glutamine metabolism by triple negative breast cancer cells promotes breast tumor innervation and
brain metastasis. To test this hypothesis, we will bioengineer 3D culture platforms to closely mimic the mammary
tumor microenvironment. To do so, we will develop a tissue engineered model of the mammary tumor
microenvironment using decellularized mammary tissue as a scaffold to culture 4T1 mouse triple negative breast
cancer cells, mouse primary adipose stromal cells (ASCs) and mouse primary dorsal root ganglia (DRG) (Aim
1). We will analyze glutamine metabolic profile of the 3D model of breast tumor innervation by using state-of-
the-art metabolism profiling tools and exploiting the endogenous autofluorescence of metabolic cofactors (Aim
2). Finally we will assess the influence of breast tumor innervation on brain metastasis via immunofluorescence
in vitro and in vivo implantation of DRG neurite-conditioned 4T1s and ASCs (Aim 3). Inhibitors of glutamine
synthesis, consumption and glutamate production/function will be tested for their ability to block innervation and
the results will be analyzed in the Data Science Core to evaluate glutamine effects on breast tumor innervation
in vitro. We will utilize the three cores (Data Science Core for data analysis, Imaging & Spectroscopy Core
for 3D volumetric time-lapse confocal and multiphoton imaging, and Bioenergetics Core for metabolic profiling
of in vitro cultures) to achieve strong rigor in study design, execution, analysis and interpretation and improve
our understanding of breast tumor innervation and brain metastasis. Combined with mentoring by Dr. Tim
Muldoon and Dr. Robert Griffin, as well as the AIMRC’s senior mentoring committee and other center ...

## Key facts

- **NIH application ID:** 10574565
- **Project number:** 5P20GM139768-03
- **Recipient organization:** UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
- **Principal Investigator:** Younghye Song
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $216,294
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10574565

## Citation

> US National Institutes of Health, RePORTER application 10574565, Investigating the role of glutamine metabolism in breast tumor innervation and brain metastasis (5P20GM139768-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10574565. Licensed CC0.

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