# MOSAIC: Targeting the Tissue State

> **NIH NIH U54** · MAYO CLINIC ARIZONA · 2024 · $12,590

## Abstract

SUMMARY: PROJECT 1: TARGETING GLIOMA TISSUE STATES
Glioblastoma (GBM) displays extensive cellular heterogeneity which represents a major obstacle for effective 
treatment. This cellular heterogeneity not only consists of multiple tumor cell mutation factors that drive distinct 
tumor cell behavior, but also impacts various non-tumor cells, contributing to tumor initiation, progression, and 
treatment response. In fact, GBM’s microenvironment is multifaceted and consists of soluble factors, extracellular 
matrix components, tissue-resident cells (neuron, astrocytes, endothelial cells, pericytes, etc.) and resident (e.g. 
microglia) or recruited (e.g. bone-marrow derived macrophages) immune cells. Importantly, changes in the 
cellular composition and cellular phenotypes can alter GBM tissue states to drive tumor growth and therapeutic 
resistance. Thus, identifying the unique cellular composition and deciphering the multifaceted bidirectional 
network between tumor cells and tumor microenvironment signals in various GBM tissue states can lead to 
identification of novel therapeutic strategies. 
Our preliminary studies using single nucleus RNAseq of pre- and post-treatment GBM has identified 3 tissue 
states, corresponding to patterns of cohabitation of tumor and non-tumoral cell subpopulations. These 
correspond to infiltrated brain, highly cellular proliferating tumor, and astrocytic / inflamed reactive tissue, which 
is observed in the post-treatment samples and enriched in specific populations of myeloid cells and 
mesenchymal glioma cells. Co-habitation of specific non-tumor cellular phenotypes in the glioma 
microenvironment may influence glioma states signatures (astrocyte-like/mesenchymal, progenitor, proliferative) 
that associate with tumor progression and therapeutic response. The goal of this project is to define the patterns 
of cellular cohabitation associated with the tissue states and the cross-talk signals that influence local tissue 
state, phenotypic expression, transitions and disease progression. Because of its known role in cross-talk 
between specific populations in GBM, we will initially test the effects of targeting TWEAK-Fn14 signaling to drive 
changes in tissue state. We hypothesize that targeting this as well as other key cross-talk signaling pathways
will induce tissue state transitions with corresponding alterations in cellular populations that will render tumors 
more sensitive to therapeutic vulnerabilities and can be leveraged to slow tumor growth/progression. 
To investigate the potential impact of such key states and their cross-talk, we propose three aims. Aim 1 focuses 
on refining our understanding of glioma tissue states in both the pre- and post- treatment setting. Aim 2
investigates cross talk between the glioma cells and their microenvironment and how it may influence 
progression. Aim 3 looks more locally at how cross-talk perturbations may impact tissue state transition.

## Key facts

- **NIH application ID:** 11186082
- **Project number:** 3U54CA274504-02S1
- **Recipient organization:** MAYO CLINIC ARIZONA
- **Principal Investigator:** Nhan L Tran
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $12,590
- **Award type:** 3
- **Project period:** 2023-09-18 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11186082

## Citation

> US National Institutes of Health, RePORTER application 11186082, MOSAIC: Targeting the Tissue State (3U54CA274504-02S1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/11186082. Licensed CC0.

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