# Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion.

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $442,928

## Abstract

Project Summary
New therapies are urgently needed for patients with malignant gliomas, which are highly invasive and lethal brain
tumors. Patients with glioblastoma (GBM) die within 1-2 years of diagnosis despite current conventional
therapies, including surgery, radiation and chemotherapy. A major driver of tumor recurrence is the infiltrative
nature of the glioma cells into adjacent normal brain, which is driven by activation of a mesenchymal transcription
program. This mesenchymal transition is activated through extracellular stimulation of cell surface receptors by
growth factors such as TGFβ1. The overall purpose of the present project is to investigate the role of adhesion
G protein-coupled receptor B1 (ADGRB1/BAI1) in the mesenchymal switch and invasion, and explore new
therapies for GBM based on the related mechanisms. ADGRB1 is an orphan adhesion GPCR specifically
expressed in the brain. We previously showed that ADGRB1 expression is significantly reduced in patients with
GBM through epigenetic silencing, suggesting that ADGRB1 loss may facilitate tumor formation. Our new
preliminary data show that low ADGRB1 expression correlates with invasion and poor outcome in glioma
patients. Restoration of ADGRB1 expression in GBM cells suppresses the mesenchymal phenotype in culture
and mice xenografts. Our pilot studies further suggest ADGRB1 can inhibit TGFβ1-driven mesenchymal
transition through a WxLWxLW motif in its first thrombospondin type 1 repeat (TSR1). This motif mediates
ADGRB1 binding to the latent TGFβ1 complex and prevents TGFβ1 maturation. Based on these results, we
hypothesize that ADGRB1 acts as a brain tumor suppressor by blocking the TGFβ1-mediated mesenchymal
switch and that restoration of its expression with epigenetic therapy will represent a novel therapeutic intervention
for GBM. To test our hypothesis, we propose the following aims: (i) define how ADGRB1 negatively regulates
the mesenchymal transition and glioma invasion, (ii), determine how BAI1 antagonizes TGFβ1 pro-mesenchymal
signaling and (iii) evaluate whether epigenetic restoration of BAI1 expression can inhibit glioma cell invasion in
vitro and in vivo, and augment survival post-operation. These studies are important as we identified a specific
region in the extracellular domain of BAI1 that antagonizes TGFβ1 maturation and the glioma mesenchymal
switch, providing a new mechanism for antagonizing this oncogenic pathway that can be exploited
therapeutically. These findings support targeting this new pathway in patients whose cancers are driven by
mesenchymal transition.

## Key facts

- **NIH application ID:** 10488569
- **Project number:** 5R01NS117666-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** ERWIN G. VAN MEIR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,928
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488569

## Citation

> US National Institutes of Health, RePORTER application 10488569, Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion. (5R01NS117666-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10488569. Licensed CC0.

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