A single-cell map of immune and structural cells inside benign brain tumours will be built to identify inflammatory signals that drive hearing loss and tinnitus. Vestibular schwannomas are non-cancerous growths on the nerve connecting the ear to the brain. They cause progressive hearing loss and tinnitus in thousands of people each year. Current treatments—surgery and radiotherapy—carry risks of stroke, nerve damage, and death, and often worsen hearing. The molecular triggers behind tumour growth and hearing damage remain unknown, especially the role of the tumour’s supportive cells, called fibroblasts and macrophages. The research team will analyse tumour tissue and adjacent inner-ear nerve tissue from patients undergoing surgery. Using single-cell RNA sequencing and spatial transcriptomics, they will create a detailed atlas of which cell types are present and where they sit. They will then test whether these cells undergo metabolic reprogramming—a shift in how they use energy—and look for inflammatory markers in both tumour tissue and blood that correlate with tumour size, hearing loss severity, and tinnitus. If successful, this work could identify new drug targets that slow tumour growth or protect hearing without the risks of surgery or radiation. It may also yield blood-based biomarkers to monitor disease progression without repeated scans.
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Background: Vestibular Schwannoma (VS) are histologically benign but cause significant morbidity as they grow in close proximity to the great vessels of the neck, several cranial nerves and can cause brain compression. The treatment options include surgery and radiotherapy, with additional risks (strokes, cranial nerve palsies) and mortality. Importantly, VS are an important cause of hearing loss and tinnitus. There is therefore a need to develop treatment strategies with better safety and hearing preservation profile. The molecular and cellular mechanisms (especially pertaining to stromal cells) that drive VS pathogenesis are poorly understood and are the focus of the proposed work. Hypothesis: Inflammatory and metabolic changes in fibroblasts and macrophages in VS microenvironment drive tumour progression and associated hearing loss/tinnitus. Aims: Construction of a cellular and spatial atlas of fibroblast and macrophage subsets in VS using single cell RNA sequencing and spatial transcriptomics. Examine whether fibroblasts and macrophages undergo metabolic reprogramming in VS. Explore potential biomarkers in tumour tissue and peripheral blood that correlate with VS tumour growth/size, hearing loss and tinnitus. Study design: Patients undergoing surgical removal of VS will be recruited into the study. Following informed consent, tumour tissue as well as adjacent vestibular neuroepithelium will be collected and processed. We will use single cell RNA sequencing and spatial transcriptomics to create a map of individual cell types in VS and vestibular neuro-epithelium tissue to identify pathogenic cell types and their temporal profile in tumorigenesis. Cell sorting, flow cytometry, tissue immunostainings, immunohistochemistry will be used to characterize the phenotype and function of stromal cells in VS. We will assess metabolic reprogramming of the stromal cells using techniques such as Sea-horse analysis. The inflammatory and metabolic targets identified will be quantified in tumour tissue and peripheral blood and correlated with tumour size/growth, hearing level and tinnitus indices.
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