# Tissue Factor as a Key Determinant of IDH1 Mutant versus IDH1 Wild-type Glioma Thrombosis and Malignancy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $345,625

## Abstract

PROJECT SUMMARY/ABSTRACT
Infiltrative glioma is the most common type of primary brain tumor in adults, causing over 17,000 deaths in the
United States every year. Approximately 20-30% of infiltrative gliomas contain mutations in isocitrate
dehydrogenase 1 (IDH1mut). IDH1mut causes global DNA hypermethylation, which contributes to gliomagenesis.
Yet, IDH1mut gliomas are significantly less aggressive than gliomas lacking this mutation. It has remained unclear
how DNA hypermethylation leads to this unique phenotype. Gliomas often produce blood clots (thrombi) within
the tumor and throughout the bloodstream. These thrombi have long been known to be predictors of poor
outcome. We recently reported that IDH1mut gliomas produce far fewer thrombi; our data strongly indicate that
methylation-induced suppression of F3, the gene encoding Tissue Factor (TF), is the reason why. TF is a
powerful procoagulant that, when produced and released by cancers, causes venous thromboemboli (VTE). This
debilitating phenomenon occurs in ~25% of glioma patients, but never when IDH1mut is present. In addition to
triggering thrombosis, TF binds and activates protease-activated receptor 2 (PAR2), a transmembrane receptor
expressed by cancer cells that signals through multiple intracellular pathways to promote tumor malignancy. Our
data show that: (i) among all genes that directly participate in blood clotting, F3 mRNA levels have the strongest
inverse relationship with IDH1mut; (ii) F3 methylation is significantly higher in IDH1mut gliomas than IDH1wt gliomas;
(iii) TF protein levels are consistently lower in IDH1mut gliomas than IDH1wt gliomas; (iv) circulating TF is lower in
patients with IDH1mut gliomas than IDH1wt gliomas; (v) high circulating TF correlates with increased VTE risk; (vi)
patient-derived glioma cells with endogenous IDH1mut produce smaller and fewer venous thrombi than IDH1wt
gliomas in xenograft mouse models; (vii) suppression of TF in IDH1wt gliomas greatly reduces their in vitro and
in vivo malignancy; (viii) patients whose gliomas express low TF have more than double the median survival of
patients whose gliomas express high TF, independent of IDH1mut. Thus, we hypothesize that methylation-
induced suppression of TF is a critical determinant of the less thrombogenic, and less malignant, IDH1mut
phenotype. In Aim 1, we will conclusively establish that F3 hypermethylation is the mechanism by which IDH1mut
suppresses TF expression. In Aim 2, we will modulate the expression of TF in a series of patient-derived IDH1wt
and IDH1mut glioma cells, observing the effects on tumor-induced thrombosis and malignancy in cell cultures and
in engrafted mice. In Aim 3, we will use molecular and pharmacologic approaches to investigate the therapeutic
potential of blocking TF-PAR2 signaling in gliomas. Further, we will prospectively evaluate the utility of
determining circulating TF levels, along with other clinical, blood-based, and tissue-based biomarkers, to create
the ...

## Key facts

- **NIH application ID:** 10197235
- **Project number:** 5R01NS102669-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Craig Michael Horbinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,625
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197235

## Citation

> US National Institutes of Health, RePORTER application 10197235, Tissue Factor as a Key Determinant of IDH1 Mutant versus IDH1 Wild-type Glioma Thrombosis and Malignancy (5R01NS102669-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10197235. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*