# Tissue factor regulation of receptor tyrosine kinases in glioblastoma

> **NIH NIH F30** · NORTHWESTERN UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary
Glioblastoma (GBM) is the most common cancer arising in the adult brain, yet despite years of intensive
research, it remains a fatal disease. Major barriers to improving GBM treatment include the cancer stem cell
(CSC) phenotype, a self-renewing behavior that facilitates tumor recurrence and therapy resistance, and the
profoundly immunosuppressive microenvironment of GBM. Activation of receptor tyrosine kinases (RTKs) is
implicated in both of these processes. A better understanding of what triggers RTK signaling, and how it leads
to the CSC phenotype and immunosuppression in GBM, is essential for improving patient care. Our preliminary
and published data have established the importance of Tissue Factor (TF) in GBM malignancy. TF is a protein
involved in blood clotting, but it can also bind and activate protease-activated receptor 2 (PAR2), a
transmembrane G protein-coupled receptor that promotes cell proliferation, migration, and angiogenesis. This
TF-induced process exists to facilitate wound healing, but can be harnessed by cancers to increase their
malignancy. In many cancers, including glioma, high TF expression correlates with worse patient survival, and
our recently published work demonstrated that suppression of TF greatly attenuates the aggressiveness of GBM.
In our preliminary and published data, we found that TF is an upstream activator of multiple classes of RTKs,
including class I (EGFR), II (IGF-IR), III (PDGFRβ), IV (VEGFR-2), and X (Axl). We also found that TF acts
through an intracellular pathway to do so, and that TF is a major contributor to the CSC phenotype in GBM.
Furthermore, we found that TF can upregulate the expression of PD-L1, which is a protein found on GBM and
myeloid cells that when bound can suppress antitumor immunity by inhibiting the activity and proliferation of T
cells. However, the mechanisms whereby TF exerts these effects in GBM are still unclear. Our overarching
hypothesis is that TF promotes CSC subpopulations, and suppresses antitumor immunity, through PAR2-
mediated activation of the intracellular domain of RTKs. In the first Specific Aim of the proposal, we will
investigate the mechanisms by which TF stimulates RTK signaling by determining what constitutes the binding
partner complex that activates RTKs, and by examining the detailed role of TF and PAR2 in RTK activation. The
second Specific Aim will focus on the role that TF-mediated RTK activation has on the CSC phenotype in GBM.
The third Specific Aim will investigate the role of TF-PAR2-RTK signaling in immunosuppression in GBM, and if
therapeutics can inhibit this process and prolong survival of mice. The long-term goals of the proposed work are
to improve the understanding of how TF promotes malignant behavior, elucidate a new mechanism by which
RTKs are activated in cancer, and to demonstrate the therapeutic potential of blocking TF-PAR2 signaling.

## Key facts

- **NIH application ID:** 10068507
- **Project number:** 1F30CA243288-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Michael Raymond Drumm
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068507

## Citation

> US National Institutes of Health, RePORTER application 10068507, Tissue factor regulation of receptor tyrosine kinases in glioblastoma (1F30CA243288-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10068507. Licensed CC0.

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