# Deciphering the role of Microglia in Glioblastoma

> **NIH NIH R56** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $554,102

## Abstract

Glioblastomas are the most common primary malignant brain tumors. Total neurosurgical resection of
glioblastomas is not possible, and tumors invariably recur even following resection, chemo- and radiotherapy.
Despite extensive research into the biology of glioblastomas, there has been no change in the standard of care
for ~20 years and the median lifespan from time of diagnosis to death remains dismal at ~15 months. This
highlights the need for identifying new targets for therapy of these devastating tumors.
 Glioblastomas are characterized by extensive infiltration of microglia; the main resident innate immune
cells of the brain. Yet, despite their large presence, microglia fail to keep the tumor in check and appear to
promote tumor growth. The exact mechanism(s) of this pro-tumor role of microglia remain incompletely
understood. Using an approach that allows us to selectively identify and isolate microglia present within the
tumor (vs. those in the same brain but outside the tumor), we determined the transcriptomes of these
Glioblastoma Associated Microglia (GAMi) by RNASeq in a murine model of glioblastoma. We found that
glioblastomas reprogram microglial transcriptional networks by downregulating pathways potentially involved in
recognizing and killing tumor cells. Specifically, we found that GAMi have downregulated: (a) genes potentially
involved in immune sensing and phagocytosis of glioblastoma cells and (b) transcripts potentially involved in
direct tumor killing. We also found that most of the changes observed in GAMi may be driven by a microglia
specific pathway. We obtained similar findings when we analyzed datasets from human glioblastoma patients.
 In this application, we propose to test which of these microglial transcriptional changes are functionally
important in regulating tumor growth using three preclinical mouse glioblastoma models and a co-culture model
of patient-derived human glioblastoma and iPSC-derived microglia. We will also identify the precise microglial
pathway that regulates these processes. To achieve this, we propose three specific aims. In aim 1, we will
determine if GAMi have reduced functional capacity to recognize and phagocytose tumor cells, and the effect of
such reduced capacity on tumor growth. In aim 2, we will determine if GAMi have reduced functional capacity to
kill tumor cells, and the effect of such reduced capacity on tumor growth. In aim 3, we determine the specific
microglial pathway that regulates microglial sensing and phagocytosis of glioblastoma cells, direct killing of tumor
cells and whether targeting such pathway will regulate overall tumor growth. Our studies would provide proof of
concept that these pathways can be used as potential effective targets for therapy of this devastating tumor.

## Key facts

- **NIH application ID:** 10416151
- **Project number:** 1R56NS123271-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JOSEPH EL-KHOURY
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $554,102
- **Award type:** 1
- **Project period:** 2021-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416151

## Citation

> US National Institutes of Health, RePORTER application 10416151, Deciphering the role of Microglia in Glioblastoma (1R56NS123271-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10416151. Licensed CC0.

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