Abstract
Vestibular schwannomas (VSs), which develop from Schwann cells (SCs) of the vestibular
nerve, are the most prevalent benign tumors of the cerebellopontine angle and internal
auditory canal. Despite advances in treatment, the cellular components and mechanisms
of VS tumor progression remain unclear. Here, we performed single-cell RNA-seq on
clinically surgically isolated VS samples and clarified their cellular composition
in a sophisticated manner, including the heterogeneous Schwann cell subtypes. Advanced
bioinformatics analysis also revealed the associated biological functions, pseudotime
trajectory and transcriptional network of the SC subgroups. Furthermore, we also found
that there was tight intercellular communication between Schwann cells and tumor-associated
fibroblasts via integrin and growth factor signaling and that the gene expression
differences in SCs and fibroblasts determined the heterogeneity of cellular communication
in different individuals. Our findings suggested a microenvironmental mechanism underlying
the development of VS.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The American Journal of PathologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Vestibular Schwannomas.N Engl J Med. 2021; 384: 1335-1348
- Loss of SOX10 function contributes to the phenotype of human Merlin-null schwannoma cells.Brain. 2013; 136: 549-563
- Transcriptional profiling of mouse peripheral nerves to the single-cell level to build a sciatic nerve ATlas (SNAT).Elife. 2021; : 10
- Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity.Proc Natl Acad Sci U S A. 2020; 117: 9466-9476
- Corneal nonmyelinating Schwann cells illuminated by single-cell transcriptomics and visualized by protein biomarkers.J Neurosci Res. 2021; 99: 731-749
- c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration.Neuron. 2012; 75: 633-647
- Dynamic Environmental Physical Cues Activate Mechanosensitive Responses in the Repair Schwann Cell Phenotype.Cells. 2021; : 10
- Disentangling glial diversity in peripheral nerves at single-nuclei resolution.Nat Neurosci. 2022; 25: 238-251
- Familial unilateral vestibular schwannoma is rarely caused by inherited variants in the NF2 gene.Laryngoscope. 2019; 129: 967-973
- Therapy of Sporadic and NF2-Related Vestibular Schwannoma.Cancers (Basel). 2020; 12
- EANO guideline on the diagnosis and treatment of vestibular schwannoma.Neuro Oncol. 2020; 22: 31-45
- Relationship of Vertigo and Postural Instability in Patients With Vestibular Schwannoma.Clin Exp Otorhinolaryngol. 2018; 11: 102-108
- Efficacy of microsurgical tumor removal for treatment of patients with intracanalicular vestibular schwannoma presenting with disabling vestibular symptoms.J Neurosurg. 2017; 126: 1514-1519
- Growth characteristics of vestibular schwannomas.Otol Neurotol. 2012; 33: 1053-1058
- Growth rate of vestibular schwannoma.J Clin Neurosci. 2016; 32: 1-8
- Determinants of Vestibular Schwannoma Growth.Otol Neurotol. 2021; 42: 746-754
- Inflammation and vascular permeability correlate with growth in sporadic vestibular schwannoma.Neuro Oncol. 2019; 21: 314-325
- Genetic landscape of sporadic vestibular schwannoma.J Neurosurg. 2018; 128: 911-922
Bachir S, Shah S, Shapiro S, Koehler A, Mahammedi A, Samy RN, Zuccarello M, Schorry E, Sengupta S: Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis. Int J Mol Sci 2021, 22.
- An update on the CNS manifestations of neurofibromatosis type 2.Acta Neuropathol. 2020; 139: 643-665
- The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling.Oncogene. 2019; 38: 6370-6381
- Constitutional rearrangements of chromosome 22 as a cause of neurofibromatosis 2.J Med Genet. 2004; 41: 529-534
- Single-cell RNA sequencing: Technical advancements and biological applications.Mol Aspects Med. 2018; 59: 36-46
- Koos Classification of Vestibular Schwannomas: A Reliability Study.Neurosurgery. 2019; 85: 409-414
- GOplot: an R package for visually combining expression data with functional analysis.Bioinformatics. 2015; 31: 2912-2914
- Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.Nat Genet. 2000; 25: 25-29
- The Gene Ontology resource: enriching a GOld mine.Nucleic Acids Res. 2021; 49: D325-d334
- Free-access copy-number variant detection tools for targeted next-generation sequencing data.Mutat Res Rev Mutat Res. 2019; 779: 114-125
- SCENIC: single-cell regulatory network inference and clustering.Nat Methods. 2017; 14: 1083-1086
- A scalable SCENIC workflow for single-cell gene regulatory network analysis.Nat Protoc. 2020; 15: 2247-2276
- Single-Nucleus RNA-Seq Is Not Suitable for Detection of Microglial Activation Genes in Humans.Cell Rep. 2020; 32108189
- Spleen glia are a transcriptionally unique glial subtype interposed between immune cells and sympathetic axons.Glia. 2021; 69: 1799-1815
- A tuned gelatin methacryloyl (GelMA) hydrogel facilitates myelination of dorsal root ganglia neurons in vitro.Mater Sci Eng C Mater Biol Appl. 2021; 126112131
- MP44-09 UNDERSTANDING PRUNE BELLY SYNDROME AT SINGLE CELL RESOLUTION.J Urol. 2021; 206: e796
- RGS5 promotes arterial growth during arteriogenesis.EMBO Mol Med. 2014; 6: 1075-1089
- The endothelial protein PLVAP in lymphatics controls the entry of lymphocytes and antigens into lymph nodes.Nat Immunol. 2015; 16: 386-396
- Identification of a dysfunctional microglial population in human Alzheimer's disease cortex using novel single-cell histology image analysis.Acta Neuropathol Commun. 2020; 8: 170
- Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy.Cell. 2020; 182 (e823): 855-871
- Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils.Sci Transl Med. 2020; 12
- Superficial neurofibromas in the setting of schwannomatosis: nosologic implications.Acta Neuropathol. 2011; 121: 663-668
- a proteolipid in glycosphingolipid enriched domains: functional implications in myelin and beyond.Prog Neurobiol. 2000; 60: 531-544
- Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain.Nat Biotechnol. 2018; 36: 70-80
- Identification of targets of tumor suppressor microRNA-34a using a reporter library system.Proc Natl Acad Sci U S A. 2017; 114: 3927-3932
- Metascape provides a biologist-oriented resource for the analysis of systems-level datasets.Nature communications. 2019; 10: 1523
- intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis.Nucleic Acids Research. 2021; 49: W317-W325
- Role of Merlin/NF2 inactivation in tumor biology.Oncogene. 2016; 35: 537-548
- Stabilization of Motin family proteins in NF2-deficient cells prevents full activation of YAP/TAZ and rapid tumorigenesis.Cell Rep. 2021; 36109596
- Critical roles of phosphoinositides and NF2 in Hippo pathway regulation.Genes Dev. 2020; 34: 511-525
- LIMCH1 suppress the growth of lung cancer by interacting with HUWE1 to sustain p53 stability.Gene. 2019; 712143963
- Myristoylated alanine-rich C kinase substrate (MARCKS): a multirole signaling protein in cancers.Cancer Metastasis Rev. 2017; 36: 737-747
- Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment.Cell Res. 2015; 25: 588-603
- Occupational Noise Exposure and Vestibular Schwannoma: A Case-Control Study in Sweden.Am J Epidemiol. 2020; 189: 1342-1347
- Stereotactic radiosurgery for management of vestibular schwannoma: a short review.Neurosurg Rev. 2021; 44: 901-904
- Retreatment of vestibular schwannoma with Gamma Knife radiosurgery: clinical outcome, tumor control, and review of literature.J Neurosurg. 2018; 129: 137-145
- The Influence of Vestibular Schwannoma Tumor Volume and Growth on Hearing Loss.Otolaryngol Head Neck Surg. 2020; 162: 530-537
- Proliferative response of microglia and macrophages in the adult mouse eye after optic nerve lesion.Invest Ophthalmol Vis Sci. 2010; 51: 2686-2696
- Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on Pathological Methods and Prognostic Factors in Vestibular Schwannomas.Neurosurgery. 2018; 82: E47-e48
- Difference in the hypoxic immunosuppressive microenvironment of patients with neurofibromatosis type 2 schwannomas and sporadic schwannomas.J Neurooncol. 2020; 146: 265-273
- Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma.Clin Cancer Res. 2017; 23: 3120-3128
- Ten years of anti-vascular endothelial growth factor therapy.Nat Rev Drug Discov. 2016; 15: 385-403
- Anger Emotional Stress Influences VEGF/VEGFR2 and Its Induced PI3K/AKT/mTOR Signaling Pathway.Neural Plast. 2016; 20164129015
- The GDNF family: signalling, biological functions and therapeutic value.Nat Rev Neurosci. 2002; 3: 383-394
- Vitamin C regulates Schwann cell myelination by promoting DNA demethylation of pro-myelinating genes.J Neurochem. 2021; 157: 1759-1773
- Peroxiredoxins, oxidative stress, and cell proliferation.Antioxid Redox Signal. 2005; 7: 768-777
- β-Elemene enhances radiosensitivity in non-small-cell lung cancer by inhibiting epithelial-mesenchymal transition and cancer stem cell traits via Prx-1/NF-kB/iNOS signaling pathway.Aging (Albany NY). 2020; 13: 2575-2592
- Genome Instability Profiles Predict Disease Outcome in a Cohort of 4,003 Patients with Breast Cancer.Clin Cancer Res. 2020; 26: 4606-4615
- Oxidative Phosphorylation as an Emerging Target in Cancer Therapy.Clin Cancer Res. 2018; 24: 2482-2490
- Decoding the multicellular ecosystem of lung adenocarcinoma manifested as pulmonary subsolid nodules by single-cell RNA sequencing.Sci Adv. 2021; 7
- The Emerging Hallmarks of Cancer Metabolism.Cell Metab. 2016; 23: 27-47
- Immunology Driven by Large-Scale Single-Cell Sequencing.Trends Immunol. 2019; 40: 1011-1021
- Identification of recurrent regions of chromosome loss and gain in vestibular schwannomas using comparative genomic hybridisation.J Med Genet. 2003; 40: 802-806
- Determinants of Resistance to Checkpoint Inhibitors.Int J Mol Sci. 2020; : 21
- High-grade serous tubo-ovarian cancer refined with single-cell RNA sequencing: specific cell subtypes influence survival and determine molecular subtype classification.Genome Med. 2021; 13: 111
- Stromal biology and therapy in pancreatic cancer: ready for clinical translation?.Gut. 2019; 68: 159-171
- Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts.Nature. 2019; 569: 723-728
- Cross-talk between integrin α6β4 and insulin-like growth factor-1 receptor (IGF1R) through direct α6β4 binding to IGF1 and subsequent α6β4-IGF1-IGF1R ternary complex formation in anchorage-independent conditions.J Biol Chem. 2012; 287: 12491-12500
- Tumor Biology of Vestibular Schwannoma: A Review of Experimental Data on the Determinants of Tumor Genesis and Growth Characteristics.Otol Neurotol. 2015; 36: 1128-1136
- A cell type-specific allele of the POU gene Oct-6 reveals Schwann cell autonomous function in nerve development and regeneration.Embo j. 2002; 21: 4612-4620
Article Info
Publication History
Accepted:
June 8,
2022
Received in revised form:
May 18,
2022
Received:
January 31,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Maoxiang Xu, Shengming Wang and Yumeng Jiang contributed equally to this work.
Funding
This work was supported by the National Natural Science Foundation of China (No. 81870717 to DZ Yu, No. 81971240 to F Liu), Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant (20191921 to DZ Yu) and Shanghai Municipal Commission of Science and Technology (No. 18DZ2260200 to F Liu).
CONFLICT OF INTEREST
There were no commercial or financial associations that may be considered possible conflicts of interest during the study process.
Identification
Copyright
© 2022 Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.
