# Modeling the Glioblastoma Microenvironment to Uncover Progression Mechanisms and Therapeutic Targets

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $509,921

## Abstract

In nearly all forms of human cancer, the development of necrosis is tightly linked with
malignant progression. Whether necrosis accelerates progression or is largely passive
remains an open question, yet modeling these events to establish mechanisms and
therapeutic vulnerabilities in animals has been challenging. In glioblastoma (GBM; WHO
grade IV), the most malignant primary brain tumor, the rapid, radial growth phase that
leads quickly to death is consistently preceded by the development of central necrosis.
While genetic alterations of GBM are known in great detail, the biological properties that
result from their acquisition and lead to this accelerated growth phase require deeper
investigation. The tumor microenvironment (TME) changes dramatically following the
onset of necrosis, from a sheet-like growth of infiltrating cells with relatively constant
growth properties to a highly complex and evolving 3-D microsystem composed of
diverse cell types and spatially segregated signaling networks. To better understand the
dynamic temporal and spatial changes that promote progression, we propose to
advance mouse models that closely parallel these events in human gliomas, since many
mouse models of GBM lack necrosis. We developed a novel method to induce focal
necrosis within high grade gliomas in vivo and will study TME restructuring and its
impact on glioma growth in real time using multiphoton microscopy. As translational
applications, we will demonstrate how hypoxia and necrosis promote the enrichment of
glioma stem cells (GSCs) in their peri-necrotic niche and lead to the dramatic influx of
tumor-associated macrophages (TAMs), which increase in number over 10-fold in the
human disease. We propose both genetically characterized patient-derived GBM
xenografts grown in mice with humanized immune cells, as well as an
immunocompetent RCAS/tv-a model, and will determine how antagonizing these
processes impact disease progression and outcomes. Our preliminary data and the
literature indicate substantial differences between pre-necrotic and necrotic gliomas with
regard to GSC and TAM enrichment and their impact on biological properties, but the
mechanisms and evolution have not been studied in depth, in large part due to the
absence of a credible animal model. Our model will capture glioma growth dynamics,
GSC enrichment, and TAM influx, and facilitate the development of therapies that
antagonize these mechanisms to improve outcomes.

## Key facts

- **NIH application ID:** 10146980
- **Project number:** 5R01CA247905-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** DANIEL J BRAT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $509,921
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146980

## Citation

> US National Institutes of Health, RePORTER application 10146980, Modeling the Glioblastoma Microenvironment to Uncover Progression Mechanisms and Therapeutic Targets (5R01CA247905-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10146980. Licensed CC0.

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