Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state

Thomas F. Barrett, Bhuvic Patel, Saad M. Khan, Riley D. Z. Mullins, Aldrin K. Y. Yim, Sangami Pugazenthi, Tatenda Mahlokozera, Gregory J. Zipfel, Jacques A. Herzog, Michael R. Chicoine, Cameron C. Wick, Nedim Durakovic, Joshua W. Osbun, Matthew Shew, Alex D. Sweeney, Akash J. Patel, Craig A. Buchman, Allegra A. Petti (), Sidharth V. Puram () and Albert H. Kim ()
Additional contact information
Thomas F. Barrett: Washington University School of Medicine
Bhuvic Patel: Washington University School of Medicine
Saad M. Khan: Massachusetts General Hospital and Harvard Medical School
Riley D. Z. Mullins: Washington University School of Medicine
Aldrin K. Y. Yim: Washington University School of Medicine
Sangami Pugazenthi: Washington University School of Medicine
Tatenda Mahlokozera: Washington University School of Medicine
Gregory J. Zipfel: Washington University School of Medicine
Jacques A. Herzog: Washington University School of Medicine
Michael R. Chicoine: University of Missouri School of Medicine
Cameron C. Wick: Washington University School of Medicine
Nedim Durakovic: Washington University School of Medicine
Joshua W. Osbun: Washington University School of Medicine
Matthew Shew: Washington University School of Medicine
Alex D. Sweeney: Baylor College of Medicine
Akash J. Patel: Baylor College of Medicine
Craig A. Buchman: Washington University School of Medicine
Allegra A. Petti: Massachusetts General Hospital and Harvard Medical School
Sidharth V. Puram: Washington University School of Medicine
Albert H. Kim: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted.

Date: 2024
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DOI: 10.1038/s41467-023-42762-w

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