# Bimodal EGFR signaling in glioblastoma

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $429,910

## Abstract

Abstract
Glioblastoma (GBM) is the most common primary brain cancer in adults. EGFR is expressed in the majority of
GBMs and aberrant EGFR signaling is a major driver of the malignant phenotype. Although the EGFR is
considered a prime oncogene in GBM, TCGA analysis indicates that in EGFR amplified GBMs, EGFR ligands
are tumor suppressive. Our preliminary data also suggest that ligand-activated EGFR is tumor suppressive.
The tumor suppressive effects of ligand-activated EGFR result form an unexpected suppression of invasion.
We propose that constitutive and ligand-dependent EGFR wild type signaling triggers distinct signaling
pathways. Thus, constitutive EGFR signaling promotes invasion while ligand-activated EGFR signaling turns
on proliferation and turns off invasion. We elucidate mechanisms underlying EGFR regulation of invasion and
identify BIN3, a protein known to influence the cytoskeleton, as a key suppressor of GBM invasion. We also
identify the mechanisms and biological significance of ligand-activated EGFR mediated glioma cell
proliferation. We examine the relative contribution of proliferation and invasion to tumor size and prognosis in
GBM. An improved understanding of mechanisms that drive GBM invasion is critical to improved treatment.
Furthermore, we identify tofacitinib as a drug that can activate the tumor suppressor function of EGFR by
increasing EGFR ligand, upregulating BIN3 and suppressing GBM invasion. Tofacitinib is a clinically available
and FDA approved drug. Our model holds true for GBMs that express EGFR wild type or the mutant
EGFRvIII. In Specific Aim 1: We elucidate the role of RTK transactivation in driving invasion or proliferation.
We test the hypothesis that constitutive EGFR signaling promotes EGFR invasiveness whereas ligand-induced
EGFR signaling blocks it. Constitutive EGFR signaling leads to activation of Met leading to increased
invasiveness. We also identify a TAB1-TAK1-NF- B pathway that drives GBM invasion. Ligand-activated
EGFR signaling leads to Axl activation and proliferation and decreased GBM invasiveness. In Specific Aim 2:
we uncover mechanisms used by EGFR to suppress invasiveness of GBM cells. We test the hypothesis that
BIN3 is a major negative regulator of invasion. Ligand-induced EGFR activity upregulates BIN3 and
suppresses invasion. We examine the expression patterns of BIN3, BIN3 partners, EGFR and other RTKs
networks in GBM. In Specific Aim 3 we examine the biological effects of constitutive vs. ligand induced
EGFR–RTK-BIN3 signaling on GBM invasion in an orthotopic mouse model and examine tofacitinib as a
treatment that specifically inhibits GBM invasion in ligand-poor GBMs. .

## Key facts

- **NIH application ID:** 10363582
- **Project number:** 1R01NS119225-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** AMYN HABIB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,910
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363582

## Citation

> US National Institutes of Health, RePORTER application 10363582, Bimodal EGFR signaling in glioblastoma (1R01NS119225-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10363582. Licensed CC0.

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