# Cellular plasticity and equilibrium in GBM progression

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $331,675

## Abstract

PROJECT SUMMARY
A growing body of evidence points to cancer stem cells (CSCs) as the culprit behind persisting
uncontrolled growth in several human malignancies, including one of the most lethal brain tumor
Glioblastoma (GBM). It is hypothesized that CSCs in GBM (GSCs), with similar characteristics as normal
tissue stem cells, are resistant to anti-cancer therapeutics and thus instrumental in initiating clinical
relapse. Within the tumor specific “niche”, a dynamic equilibrium exists between GSCs and lineage-
committed cancer cells. This equilibrium is maintained by regulation of cell differentiation through a
balance between asymmetric and symmetric cell division rates within the GSC compartment. This
intrinsic homoeostatic state is critical for disease progression, as shifts in the equilibrium can influence
the clinical outcome. For example, in the clinical setting GSC-rich tumors are more aggressive and
associated with poor prognosis. It is, therefore, critical to elucidate the molecular mechanisms of how the
stemness equilibrium state is maintained within the tumor microenvironment, as well as its contribution to
therapeutic resistance and disease recurrence. To this end, we developed models for anti-glioma
chemotherapy-induced recurrent GBM by using patient-derived xenograft (PDX), and investigated the
evolutionary path to recurrence. Our data demonstrated that in the recurrence model, the equilibrium
shifted toward a more stem-like state and therapy-induced interleukin 8 (IL8)-regulated epigenetic
plasticity is critical for this change. Based on this, we hypothesize that cellular plasticity-mediated fate
equilibrium shift towards a more stem-like state is responsible for the aggressiveness of
recurrent GBMs and their resistance to conventional therapy. By using matched primary and
recurrent patient GBM tissues as well as our PDX derived GBM models we now propose to investigate
the role of therapy-induced cancer stem cell niche in disease recurrence (Aim 1), elucidate the molecular
mechanisms stemness equilibrium within the tumor during and post therapy (Aim 2) and finally, examine
the role of epigenetic plasticity in therapeutic resistance and disease recurrence (Aim 3). By elucidating
the molecular mechanisms of intratumoral cell fate equilibrium and investigating how such equilibrium
can be influenced by therapy will give us insight into their role in therapeutic resistance, disease
progression as well as recurrence, and aid in identifying novel targets to prevent GBM recurrence.

## Key facts

- **NIH application ID:** 9851966
- **Project number:** 5R01NS096376-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Atique U. Ahmed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,675
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851966

## Citation

> US National Institutes of Health, RePORTER application 9851966, Cellular plasticity and equilibrium in GBM progression (5R01NS096376-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851966. Licensed CC0.

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