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

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2020 · $403,750

## Abstract

ABSTRACT
Astrocytes are important in AD pathogenesis by two major mechanisms. The first mechanism involves
interactions with neurons, microglia, and oligodendrocytes and the second is by secretion of significant
quantities of Aβ to increase amyloid burden in the brain. Both AD and brain cancer increase with age,
however, several comprehensive longitudinal studies with more than one million participants have shown an
inverse relationship between the two diseases; the risk of AD in individuals with cancer was decreased by 35%
[1-7]. Our previous work analyzed microarray datasets of AD (n=524) and glioblastoma (GBM) (n=1091)
cohorts and investigated the transcriptional signaling mediating the inverse relationship between the two
diseases [8]. We found that AD and brain cancer have common and distinct deregulated transcriptional
signals. In this supplemental study, we will focus on how tumor in the brain reduces AD pathogenesis. Our
original R01 investigates astrocyte-tumor interactions in brain metastatic tumor. We developed novel
experimental and computational approaches to study astrocyte→tumor paracrine and astrocyte→astrocyte
autocrine signals for potential therapeutic strategies for brain metastatic tumors. In AD, astrocytes are under
astrocyte→neuron paracrine and astrocyte→astrocyte autocrine regulations, which are critical in causing Aβ
over-production from both neurons and astrocytes. We will expand the R01 study to explore whether the
transcriptional changes in astrocytes upon interacting with cancer cells in the brain would offer new insights to
reduce the vicious astrocyte→neuron or astrocyte→astrocyte interactions and reduce amyloid burden in AD.
 Our central hypothesis is that the astrocyte-tumor interactions would reduce Aβ production from neurons
and astrocytes, facilitate Aβ break-down by astrocytes, or both. To test this hypothesis, we set forth the
following specific aims: 1) generate single-cell RNAseq data of astrocytes, neurons, and tumor cells from the
brain of brain metastatic model in aged mice and 2) perform astrocyte-tumor-neuron crosstalk analysis using
the CCCExplorer platform as in our original R01. These two aims can be finished in one year. We expect to
identify astrocyte-centric transcriptional signals that down-regulate Aβ production in neurons and/or astrocytes,
and up-regulate the proteasomal and phagocytic breakdown of Aβ. After the supplement study, we will further
explore: 1) the post-transcriptional change of the identified signaling molecules, including secretable ligands,
membrane receptors, and intra-cellular signaling proteins by ELISA, western blot, and immunostaining; 2) the
function of the key signaling molecules in in vitro Alzheimer’s-in-a-dish models [9, 10] as in Wong’s current NIA
R01 project on Alzheimer’s disease; and 3) the therapeutic potential of the astrocyte signaling using AD
transgenic mouse models.

## Key facts

- **NIH application ID:** 10122279
- **Project number:** 3R01CA238727-01A1S1
- **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:** $403,750
- **Award type:** 3
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122279

## Citation

> US National Institutes of Health, RePORTER application 10122279, Systematic identification of astrocyte-tumor crosstalk regulating brain metastatic tumors (3R01CA238727-01A1S1). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10122279. Licensed CC0.

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