# The role of NONO in TAZ-driven glioma malignant transformation

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $333,029

## Abstract

Project Summary
Gliomas are major primary brain tumors, of which glioblastomas (GBM) are the most common and aggressive
forms. The poor outcome of traditional treatment for these tumors demands targeted therapies based on
identified mechanisms that drive tumor development. Molecular pathology has classified GBM into subtypes,
among which the mesenchymal (MES) group is the most malignant. It is still not clear how GBM MES
differentiation is achieved. Recent studies found enrichment of tumor-associated macrophages and microglia
(TAMs) in MES GBM, suggesting that TAMs may contribute to MES differentiation and could be exploited as
therapeutic targets. Transcriptional coactivator with PDZ-binding motif (TAZ) is one of the three transcriptional
regulators in driving the GBM MES gene expression program. Aberrant TAZ activation is associated with MES
GBM. The goal of this project is to investigate the role of the TAZ-driven MES transcriptional program during
TAMs enrichment in GBM, and identify vulnerabilities of GBM MES progression for therapeutics. The first
premise of the project is that we have established two novel TAZ-driven GBM mouse models showing
enhanced expression of the MES marker and TAMs infiltration. The second premise is that we have identified
the non-POU-domain-containing, octamer-binding protein (NONO) as a novel TAZ-binding protein, which is
critical for TAZ-driven gene transcription, TAMs infiltration and GBM progression. The third premise is that
NONO expression is markedly increased in GBM compared to lower grade gliomas and is associated with TAZ
as well as shorter survival. We hypothesize that aberrant TAZ activation promotes GBM to exploit TAMs for
malignant progression, and NONO is important in this process by mediating the TAZ transcriptional activities.
We further hypothesize that NONO and TAMs could be targeted for therapeutic purposes. We propose the
following three specific aims: 1) to determine the mechanism of TAMs recruitment by TAZ-driven GBM; 2) to
demonstrate the mechanism by which NONO regulates the TAZ-driven oncogenic transcriptional program in
GBM; 3) to evaluate therapeutic effects of NONO inhibition and TAMs blockade in preclinical TAZ-driven GBM
models. We will employ a panel of established human GBM cell lines, newly isolated human GBM cells, and
mouse models of GBM. Increasing evidence suggests that TAMs contributes to the pathogenesis and
therapeutic resistance of GBM. How TAMs are enriched in MES GBM and whether TAMs blockade could
benefit therapies for these tumors is still unknown. By establishing the TAZ-driven GBM models and
demonstrating the TAZ-NONO regulatory axis in recruiting TAMs, this proposal will reveal vulnerabilities of
TAZ-driven GBM progression. Because NONO appears to be nonessential in normal physiology, the GBM-
specific vulnerabilities could be a novel avenue for therapeutics.

## Key facts

- **NIH application ID:** 10461102
- **Project number:** 5R01NS109147-05
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Wei Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $333,029
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461102

## Citation

> US National Institutes of Health, RePORTER application 10461102, The role of NONO in TAZ-driven glioma malignant transformation (5R01NS109147-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10461102. Licensed CC0.

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