# Shared mechanisms of astrocyte maturation in development and glioblastoma

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $392,106

## Abstract

Project Summary
Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults. Recent work continues to
support the idea that this cancer (like many others) echoes the proliferation and differentiation programs from
earlier developmental stages. The possibility that neurological cancers like GBM are essentially `locked in' to a
developmental program and retain the controls that instruct these cell populations during development opens
new and exciting opportunities. Furthermore, it places an emphasis on the need to identify the molecular triggers
that govern the transition of immature progenitor cells to quiescent mature astrocytes during development.
In this project we will test the hypothesis that master transcriptional regulators are sufficient for driving astrocyte
maturation and that these factors can be used to jump-start stalled maturation within GBM-astrocytes. The ability
of individual or small groups of transcription factors to drive cell fate or maturation changes has been
demonstrated in a variety of cell types, including neurons and glia. To begin, we used existing transcriptomic,
epigenomic, and DNA-binding data to identify a targeted set of candidate transcription factors that we
hypothesize catalyze the astrocyte maturation process. We will test whether these transcription factors are
capable of inducing precocious maturation in immature human astrocytes by manipulating their expression using
schemes that mirror their developmental activity. As a model system, we are using human iPSC-derived cortical
organoids, which provides a multicellular platform in which astrogenesis and maturation occurs endogenously
along a timescale analogous to what is observed in the fetal and early postnatal human brain.
We will also ask how the developmental trajectory of astrocyte maturation is perturbed in the setting of GBM by
comparing epigenomic profiles of maturing human astrocytes from the organoid system with single cell data from
surgical GBM resections. This comparison will place GBM-astrocyte differentiation in the context of the normal
developmental trajectory and reveal potential transcription factors whose absence may contribute to stalled
maturation. An important possibility in the pathobiology of gliomagenesis is that the heterogeneous mutations
accumulated within GBM-astrocytes render them unreceptive to maturation-inducing transcription factors. Thus,
in a final set of experiments, we will use isogenic iPSC lines harboring driver GBM mutations to test their influence
on the receptivity to maturation-inducing transcription factors. Together, these studies will help teach us how and
where GBM cells are stalled in their developmental programs and offer novel avenues to pursue differentiation
schemes to mitigate these deadly tumors.

## Key facts

- **NIH application ID:** 10494118
- **Project number:** 5R01NS123562-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Steven A Sloan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $392,106
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10494118

## Citation

> US National Institutes of Health, RePORTER application 10494118, Shared mechanisms of astrocyte maturation in development and glioblastoma (5R01NS123562-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10494118. Licensed CC0.

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