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Antiviral mechanisms in Brain Stem Cells in Development and Cancer

Project

Antiviral mechanisms in Brain Stem Cells in Development and Cancer

Project Details

Virus infection of brain stem cells represents a major global health concern, but also offers treatment possibilities in neurodegenerative diseases and in malignant brain tumours. For example, Zika Virus targets SOX2+ neural progenitors in the developing brain to cause microcephaly in babies born to mothers infected during pregnancy; likewise, it targets SOX2+ glioma stem cells in the most common and lethal malignant brain tumour, glioblastoma (GBM) (https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4135719). Stem cells have been shown to exploit a distinct set of antiviral mechanisms compared to somatic cells (https://doi.org/10.1016/j.cell.2017.11.018), and viral permissivity varies widely between example developing brain and glioblastoma stem cell populations. Understanding and manipulating the cell-intrinsic mechanisms underpinning antiviral resistance in brain stem cells will inform approaches to protect and exploit neural stem cell function and to ablate cancer stem cells in GBM.

This project will seek to understand and modify viral permissivity and antiviral defence mechanisms in developing brain and brain tumours, focusing on stem cell intrinsic pathways. In the first place we will  address the hypothesis that immune selection pressure on glioma stem cells during tumour development results in expansion of a mesenchymal/injury-response cell population (https://www.cell.com/cell/pdf/S0092-8674(21)00351-2.pdf) refractory to virus infection, then proceed to examine underlying mechanisms.

You will be working with human patient-derived and mouse defined mutation glioma cell models, treated with viruses and viral mimetic compounds. You will be assaying transcriptional identity and responses using qPCR and RNA sequencing, immunofluorescence and RNA smFISH, and cytokine secretion using immunoassays. The lab has access to the state-of-the-art Cambridge Stem Cell Institute imaging, FACS, sequencing and bioinformatic facilities, and to additional specialist facilities (e.g. imaging mass cytometry) in the CRUK Cancer Institute next door. We will validate results in mice in vivo and/or slice cultures prepared from  human developing brain and patient brain tumour tissue, models we have established and use routinely in the lab.

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