# Systematic identification of astrocyte-tumor crosstalk regulating brain metastatic tumors

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2020 · $369,431

## Abstract

As treatment outcomes of primary or systemic cancer sites improve, the clinical importance of brain metastasis
(BM) is growing. Twenty-four to 45 percent of all cancer patients develop BM, the majority from lung, breast or
melanoma primary cancers, but few patients with BM live longer than a year, and BM constitutes 20% of
annual cancer deaths. Ironically, recent advancement in chemotherapy has further increased the incidence of
BM because most therapeutic agents cannot effectively penetrate the blood-brain barrier (BBB) and tumor
cells find the brain as a sanctuary. Therefore, it is of paramount importance to have a deeper understanding of
mechanisms that promote BM growth, which could be specifically leveraged to overcome current limitations in
therapy.
 As opposed to the molecular mechanisms involving cancer cell–host interactions shared by multiple cancer
types that result in organ specific metastasis, a highly distinct set of structural, anatomic, physiologic and
molecular factors regulate metastasis to the brain. Astrocytes, the most common glial cell comprising ~ 50% of
all human brain cells, are a well characterized perilesional component of BM and recent discoveries, including
ours, provide compelling evidence that molecular crosstalk between astrocytes and cancer cells is integral to
BM development. Although seminal findings indicate that interactions with astrocytes occur at both early and
late stages of tumor colonization process, our understanding of the reciprocal astrocyte-cancer cell crosstalk is
limited. In preliminary studies, we have employed our Cell-Cell Communication Explorer (CCCExplorer), a
unique computational modeling tool, in identifying the novel PCDH7-EGFR, IL6-IL6R, and CCL5-CCR5
astrocyte-tumor crosstalk signaling in regulating BM. Based on these observations and in view of the secretory
nature of glial cells, we propose here to test the hypothesis that crosstalk with astrocyte-derived secreted
factors is critical for tumor cell colonization in the brain.
 Given that an even more complicated paracrine signaling network may dynamically evolve at different
stages of BM development, and the interactions could provide both anti- and pro-metastatic stimuli to cancer
cells, we will test our hypothesis through the following aims: 1) to assess therapeutic potential of the PCDH7-
EGFR, IL6-IL6R and CCL5-CCR5 paracrine signaling in BM mouse models employing gain and loss of
function and pharmacologic approaches in syngeneic mouse and human cancer xenografts; 2) to assess the
astrocyte secreted proteins in modifying the function of BBB and microglia/macrophage in early BM; 3) to
further characterize the temporally evolved astrocyte-BM cell crosstalks in a cancer type specific fashion.
 Our study is highly innovative in that (i) this study integrates knowledge and methods from both
neuroscience and cancer to identify and characterize pro- and anti-metastatic astrocyte molecular
mechanisms, their evolution during disease progres...

## Key facts

- **NIH application ID:** 9879843
- **Project number:** 1R01CA238727-01A1
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** STEPHEN TC WONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,431
- **Award type:** 1
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879843

## Citation

> US National Institutes of Health, RePORTER application 9879843, Systematic identification of astrocyte-tumor crosstalk regulating brain metastatic tumors (1R01CA238727-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879843. Licensed CC0.

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