# Microenvironmental contribution of the Choroid Plexus and Cerebral Spinal Fluid in breast to brain metastases

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $468,283

## Abstract

PROJECT SUMMARY
Breast cancer is the first most frequently diagnosed cancer and the second most common cause of death in women
worldwide. Patients with breast-to-brain metastases (BBMs) from stage IV breast carcinoma have poor prognosis,
neurological degeneration, <10-month survival, and account for 10% of all breast cancer related deaths. Metastases arise
in the brain following hematological spread of circulating mesenchymal-type cells from primary breast tumors.
Competent tumor cell “seeds”, which can adapt to the unique brain microenvironments or “soil”, will then colonize and
establish metastatic tumors. We recently showed that BBMs exhibit neuronal properties, become GABAergic, and can
utilize the neurotransmitter gamma-Aminobutyric acid (GABA) as an onco-metabolite. Our current results show that
BBMs express neuron-specific markers of synaptic connectivity/plasticity, indicating that these tumors mimic the
neuronal properties for possible cross-talk with the brain microenvironment. Accumulating evidence underlines the
importance of the brain microenvironment in the establishment and progression of metastatic cancers. The cerebrospinal
fluid (CSF) produced by choroid plexus cells (CP) bathes the brain and spine parenchyma, analogous to “water running
through rice field” --and thus serves as an initial milieu to the brain for circulating breast cancer cells that reach the central
nervous system. Although the role of the blood-brain-barrier (BBB) in breast-to-brain metastasis has been widely
studied, the contribution of the choroid plexus, the blood-CSF-barrier, and the CSF as a microenvironmental niche
has been largely unexplored. Our preliminary data suggest that breast cancer exposure to the choroid/CSF
microenvironment results in loss of epithelial to mesenchymal transition (EMT) and induction of synaptic plasticity in
BBM cells. We further show that when BBMs are seeded in the CSF, there is a global increase in the brain barrier-
permeability. We hypothesize that the choroid/CSF microenvironment contributes as a gateway for colonization,
and establishment of synaptic plasticity in breast-to-brain metastases. Using unique strengths of patient-derived
surgically resected BBM xenografts and Reeler transgenic mouse model (normally used to study synaptic plasticity in
neurodevelopment), we will investigate the potential roles of the CP/CSF tumor microenvironment: Specific Aim 1, as a
non-neuronal source of GABA that can be used as a biomarker for non-invasively early detection of BBMs; Specific Aim
2, facilitating induction of brain synaptic plasticity in BBMs; and Specific Aim 3, in impacting permeability of the blood-
brain-barrier and facilitating further metastasis through systemic circulation. The current proposal will shed further light
on understanding how metastatic breast cancer cells adapt to their neural niche and open avenues for the development of
novel therapeutic interventions for patients with brain metastases.

## Key facts

- **NIH application ID:** 9878802
- **Project number:** 5R01CA223544-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Josh Neman-Ebrahim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $468,283
- **Award type:** 5
- **Project period:** 2019-02-21 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878802

## Citation

> US National Institutes of Health, RePORTER application 9878802, Microenvironmental contribution of the Choroid Plexus and Cerebral Spinal Fluid in breast to brain metastases (5R01CA223544-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878802. Licensed CC0.

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