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Video

Preclinical Experimental Therapeutics

Session: Abstract Concurrent Session: Basic Science VI

EXTH-03 - A VEGF+ subpopulation of Schwann cells drives vestibular schwannoma tumorigenesis

Sunday, November 19, 2023
11:20 AM – 11:25 AM PT
Location: Room 109-110
Non-CME

    Oral Abstract Presenter(s)

  • David Asuzu

    National Institute of Neurological Disorders and Stroke
    Bethesda, Maryland, United States

    • Author(s)

  • SS

    Stefan Stoica

    Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, NIH
    Bethesda, Maryland, United States

  • LL

    Liyam Laraba

    University of Plymouth
    Plymouth, United Kingdom

  • MA

    Martin Arhin

    National Institute of Neurological Disorders and Stroke
    Bethesda, United States

  • JG

    Jasleen Gandhi

    National Institute of Neurological Disorders and Stroke
    Bethesda, Maryland, United States

  • DM

    Dustin Mullaney

    National Institute of Neurological Disorders and Stroke
    Bethesda, Maryland, United States

  • DM

    Debjani Mandal

    National Institute of Neurological Disorders and Stroke
    Bethesda, Maryland, United States

  • DP

    David Parkinson

    Plymouth University
    Plymouth, United Kingdom

  • Prashant Chittiboina

    National Institute of Neurological Disorders and Stroke
    Bethesda, Maryland, United States


Introduction: Up to 95% of vestibular schwannomas (VS) are sporadic, however their molecular underpinnings remain obscure.

Objective: To perform transcriptomic profiling of VS and investigate novel tumorigenic mechanisms.

Methods: We analyzed 19 VS samples (7 sporadic, 12 NF2), and performed single-cell RNA sequencing (scRNAseq, n = 4) or single-nucleus (snRNAseq, n = 15), assays for transposase-accessible chromatin (snATACseq, n = 15) and bulk DNA methylation (n = 14). CellChat was used to predict cell-cell interactions. We characterized transcription factor binding using ChIPseq. We validated our key findings at the mRNA and protein levels using RNAscope (n = 5) and multiplex immunocytochemistry (mIHC; n = 5). Mechanistic studies were conducted using NF2-null Periostin-Cre+ mice versus their Cre- control littermates.

Results: We profiled the VS transcriptome and identified markers for Schwann cells, macrophages, T cells and endothelial cells. We identified eight Schwann cell subclusters which were enriched for known markers for myelinating, immature, repair and non-myelinating subtypes. We also unexpectedly identified a subset of VS Schwann cells with high expression of VEFGA, and these cells were enriched for signaling via laminin, NCAM, NRXN and NEGR pathways. Using RNAscope and mIHC, we verified VEGFA expression in S100B+ Schwann cells. snRNAseq and snATACseq demonstrated increased TEAD1 expression in Schwann cells, as well as increased chromatin accessibility for TEAD family transcription factor motifs. We used ChIPseq to confirm increased TEAD1 binding at the promoters of 714 genes including VEGFA. NF2-null Periostin-Cre+ mice developed spontaneous schwannomas within their dorsal root ganglia which showed increased vegfa expression, and this was partly reversible using a novel pharmacological TEAD inhibitor in-vivo.

Conclusions: We performed detailed epigenetic and transcriptomic profiling of sporadic and NF2-associated VS and uncovered TEAD1-mediated overexpression of VEGFA in a subset of VS Schwann cells. TEAD inhibition may constitute a novel therapeutic target for VS.