# Endothelial plasticity in glioma vascularization and therapy resistance

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $398,055

## Abstract

Project Summary
Glioblastoma (GBM), the grade IV glioma, is among the most lethal of human malignancies, distinguished
by prominent vascularity. GBM is the most aggressive primary brain tumor with a current median survival of
about 14-16 months, largely due to its high resistance to conventional cytotoxic therapies. Overgrown
vasculature characterizes the tumor microenvironment that fuels GBM progression and induces vascular
niche-mediated therapeutic resistance. However, current anti-vascular therapy that primarily targets pro-
angiogenic factors including VEGF, albeit initially groundbreaking, has encountered major difficulties and
failures in treating most malignant solid tumors including GBM, likely due to insufficient eradication or
functional inhibition of tumor-associated endothelial cells (ECs). Our recent studies suggest that EC
plasticity by genetic reprogramming is a driving force that induces EC resistance to anti-angiogenic and
cytotoxic treatments. Here, our preliminary study by single-cell transcriptome analysis of tumor-associated
ECs reveals that ECs acquire mesenchymal and stemness-like gene signature in a genetically engineered
mouse GBM model. Utilizing human specimens and EC lineage-tracing systems, our studies reveal robust
treatment resistance in GBM-associated ECs. Our in vitro and in vivo data suggest that genetic reprogramming
into mesenchymal stem cell (MSC)-like cells induces EC chemoresistance through Wnt activation in GBM.
Therefore, we hypothesize that mesenchymal and stemness-like genetic reprogramming in tumor ECs
induces therapy resistance in GBM. We will test this hypothesis by pursuing the following aims: 1) Define
the molecular mechanism underlying EC plasticity and treatment resistance with a focus on Wnt activation;
2) Determine the in vivo role of c-Met/Wnt-mediated EC plasticity in tumor progression; and 3) Test
experimental therapy that combines EC plasticity inhibition with radio/chemotherapy or anti-angiogenic
therapy in orthotopic mouse GBM models. Successful completion of the proposed work will provide novel
insights into tumor microenvironment-dependent treatment resistance, and may lead to development of a
new therapeutic strategy by targeting endothelial plasticity in cancer.

## Key facts

- **NIH application ID:** 10116668
- **Project number:** 2R01NS094533-06A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Yi Fan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,055
- **Award type:** 2
- **Project period:** 2015-09-30 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116668

## Citation

> US National Institutes of Health, RePORTER application 10116668, Endothelial plasticity in glioma vascularization and therapy resistance (2R01NS094533-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116668. Licensed CC0.

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