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UK funding (£797,224): The role of Nrf2 in the tumour microenvironment of IDH wild-type glioma Ukri1 Nov 2022 UK Research and Innovation, United Kingdom
Overview
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The role of Nrf2 in the tumour microenvironment of IDH wild-type glioma
| Abstract | High-grade IDH wild-type gliomas are complex and devastating brain tumours, for which in spite of multiple modes of treatment, including surgery, chemotherapy and radiation therapy, survival times remain very short, on average of ~14 months. Macrophages and microglia are types of immune cells that have been shown to associate with glioma tumours and actively promote glioma growth. However, how they achieve their tumour-promoting activity is not clear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a protein that is known as the master regulator of the cellular redox homeostasis. Nrf2 is activated by itaconate, a compound produced in mitochondria when macrophages are stimulated by various pathogens, or when macrophages come in contact with tumours cells. The activated Nrf2 then suppresses production of a plethora of factors (known as cytokines and chemokines) that promote inflammation, and thus Nrf2 activation plays a crucial role in the resolution of inflammation and in preventing chronic inflammation, which could otherwise lead to cell death and tissue damage. Here, we propose that association with glioma cells increases the levels of itaconate in macrophages and microglia, which in turn activates Nrf2, creating an anti-inflammatory environment that favours tumour growth. We aim to answer the following research questions: 1. What are the molecular mechanisms that, upon association with glioma cells activate Nrf2 in brain macrophages and microglia? How does Nrf2 affect the interactions between glioma cells and brain macrophages and microglia? 2. Does association with glioma cells activate Nrf2 in macrophages and microglia in a zebrafish model? How? At which stages during tumour development does this occur? To achieve these aims, we will use macrophage and microglia cells with different levels of Nrf2 activity. We will expose these immune cells to media from glioma cells, or grow them together with glioma cells, and quantitatively determine the expression of pro- and anti-inflammatory factors. We will then assess the effect of macrophage and microglia cells with different levels of Nrf2 on glioma cell growth, migration and invasion. Using zebrafish glioma models, combined with live imaging, we will analyse glioma development and determine the effect of Nrf2 (activation or suppression) on the interactions between macrophages and tumour cells, and on the growth of the tumour cells. This knowledge will open possibilities to suppress the pro-tumoural activity of macrophages and microglia, and design effective anti-cancer treatments. If as hypothesized, Nrf2 activation in macrophage and microglia cells is responsible for promoting glioma development, the availability of compounds that inhibit the activity of Nrf2, provides an exciting opportunity to test their effect on glioma development in preclinical models and ultimately, in clinical trials. |
| Category | Research Grant |
| Reference | MR/W023806/1 |
| Status | Active |
| Funded period start | 01/11/2022 |
| Funded period end | 31/01/2026 |
| Funded value | £797,224.00 |
| Source | https://gtr.ukri.org/projects?ref=MR%2FW023806%2F1 |
Participating Organisations
| University of Dundee |
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: University of Dundee, Dundee.
