# Biophysical Interrogation of Signals that Drive GBM Invasion

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $425,140

## Abstract

One major issue confounding successful treatment of glioblastoma multiforme (GBM) is the presence of highly
invasive cells disseminating into the brain parenchyma. These cells evade surgical resection and often spread
distally in brain parenchyma. Multiple and spatially distinct heterotypic populations exist within a single GBM,
giving rise to the disease’s genetic heterogeneity and leading to complex cell intrinsic and extrinsic
mechanisms of invasion. Amplification of the epidermal growth factor receptor (EGFR), a hallmark mutation
present in 60% of cases, most often occurs in a heterogeneous manner and is frequently associated with
deletion of exons 2-7, creating a constitutively active mutant, EGFRvIII. While significant focus has been
placed on its kinase activity, comparatively little is known about EGFRvIII’s ability to enhance migration via
interaction with adhesion receptors. Our preliminary data supports a dual role for EGFRvIII where it interferes
with intrinsic adhesion receptors and also recruits non-transformed counterparts via extrinsic signaling to
reduce adhesion of a mixed population. Based on our findings, we hypothesize that this difference in adhesive
activity is due to differential signaling associated with EGFRvIII, and that this receptor conveys this phenotype
to non-transformed counterparts through cytokine production (Inda, Genes & Dev, 2010; Zanca, Genes & Dev,
2017) to cooperatively invade parenchyma. With this hypothesis, we will use adhesion measurement
technologies to dissect cell intrinsic EGFR-mediated invasion mechanisms; given the heterogeneity within
tumors, we will also combine newly developed adhesion sorting technologies with high throughput sequencing
technologies to identify cell extrinsic mechanisms and targets for subsequent intervention. The following lines
of experimentation will be carried out: 1) implementation of biophysical assays and signaling pathway analyses
to interrogate how cell intrinsic activity of EGFRvIII leads to labile adhesion and an invasive phenotype; 2)
biochemical and functional analysis of the EGFRvIII cell extrinsic, secretome-mediated education of wtEGFR
cell adhesive phenotype; 3) expression and epigenetic analyses on adhesion-sorted populations will be used
to define a migratome signature, its stability in wtEGFR cells after exposure to the EGFRvIII secretome, and
the ability of “educated” wtEGFR to propagate that epigenetic signature to naïve wtEGFR cells.

## Key facts

- **NIH application ID:** 9981229
- **Project number:** 1R01NS116802-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Adam J Engler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,140
- **Award type:** 1
- **Project period:** 2020-05-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981229

## Citation

> US National Institutes of Health, RePORTER application 9981229, Biophysical Interrogation of Signals that Drive GBM Invasion (1R01NS116802-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9981229. Licensed CC0.

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