Spatially resolved transcriptomics of benign and malignant peripheral nerve sheath tumors
Neuro-Oncology, vol. 27, pp. 2073–2087
Abstract
BACKGROUND: Peripheral nerve sheath tumors (PNSTs) encompass entities with different cellular differentiation and degrees of malignancy. Spatial heterogeneity complicates the diagnosis and grading of PNSTs in some cases. In malignant PNST (MPNST) for example, single-cell sequencing data has shown dissimilar differentiation states of tumor cells. Here, we aimed to determine the spatial and biological heterogeneity of PNSTs. METHODS: We performed spatial transcriptomics on formalin-fixed paraffin-embedded diseased peripheral nerve tissue. We used spatial clustering and weighted correlation network analysis to construct niche-similarity networks and gene expression modules. We determined differential expression in primary pathologies, analyzed pathways to investigate the biological significance of identified meta-signatures, integrated the transcriptional data with histological features and existing single-cell data, and validated expression data by immunohistochemistry. RESULTS: We identified distinct transcriptional signatures differentiating PNSTs. Immune cell infiltration, APOD, and perineurial fibroblast marker expression highlighted the neurofibroma component of hybrid PNSTs (HPNSTs). While APOD was evenly expressed in neurofibromatous tumor tissue in both, HPNST and pure neurofibromas, perineurial fibroblast markers were evenly expressed in HPNST, but restricted to the periphery in plexiform neurofibromas. Furthermore, we provide a spatial cellular differentiation map for MPNST, locating Schwann cell precursor and neural crest-like cells as well as those with mesenchymal transition. CONCLUSIONS: This pilot study shows that applying spatial transcriptomics to PNSTs provides important insight into their biology. It helps establish new markers and provides spatial information about the cellular composition and distribution of cellular differentiation states. By integrating morphological and high-dimensional molecular data it can improve PNSTs classification in the future.
Authors 17
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Affiliation as printed
Institute of Neuropathology, Uniklinik RWTH Aachen , Aachen ,
Institute of Neuropathology, Uniklinik RWTH Aachen, Aachen , Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen
Affiliation as printed
Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Neurosurgery, Medical Center, University of Freiburg , Freiburg ,
Faculty of Medicine, Freiburg University , Freiburg ,
Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg , Freiburg ,
Department of Neurosurgery, Medical Center, University of Freiburg , Germany
Faculty of Medicine, Freiburg University, Germany
Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg
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Affiliation as printed
Institute of Neuropathology, Uniklinik RWTH Aachen , Aachen ,
Institute of Neuropathology, Uniklinik RWTH Aachen, Aachen , Germany
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Affiliation as printed
Institute of Neuropathology, Uniklinik RWTH Aachen , Aachen ,
Institute of Neuropathology, Uniklinik RWTH Aachen, Aachen , Germany
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Affiliation as printed
Institute of Neuropathology, Uniklinik RWTH Aachen , Aachen ,
Institute of Neuropathology, Uniklinik RWTH Aachen, Aachen , Germany
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Affiliation as printed
Institute of Neuropathology, Uniklinik RWTH Aachen , Aachen ,
Institute of Neuropathology, Uniklinik RWTH Aachen, Aachen , Germany
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Technical University of Munich
Affiliation as printed
Institute of Pathology, Technical University Munich , Munich ,
Institute of Pathology , Technical University Munich, Germany
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Affiliation as printed
Department of Neurosurgery, University Hospital Ulm , Günzburg,
Department of Neurosurgery, University Hospital Ulm , Günzburg, Germany
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Affiliation as printed
Institute of Pathology, University Hospital Ulm , Ulm ,
Institute of Pathology , University Hospital Ulm, Germany
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University of Freiburg · Friedrich-Alexander-Universität Erlangen-Nürnberg · University Medical Center Freiburg · Universitätsklinikum Erlangen
Affiliation as printed
Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Erlangen ,
Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg , Freiburg ,
Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Neurosurgery, Medical Center, University of Freiburg , Freiburg ,
Faculty of Medicine, Freiburg University , Freiburg ,
Department of Neurosurgery, Medical Center, University of Freiburg , Germany
Faculty of Medicine, Freiburg University, Germany
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Neurosurgery, Medical Center, University of Freiburg , Freiburg ,
Faculty of Medicine, Freiburg University , Freiburg ,
Department of Neurosurgery, Medical Center, University of Freiburg , Germany
Faculty of Medicine, Freiburg University, Germany
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Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen
Affiliation as printed
Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Erlangen ,
Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Department of Neurosurgery, Medical Center, University of Freiburg , Freiburg ,
Faculty of Medicine, Freiburg University , Freiburg ,
Department of Neurosurgery, Medical Center, University of Freiburg , Germany
Faculty of Medicine, Freiburg University, Germany
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Affiliation as printed
Institute of Neuropathology, Uniklinik RWTH Aachen , Aachen ,
Institute of Neuropathology, Uniklinik RWTH Aachen, Aachen , Germany
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Dieter Henrik Heiland corresponding
Northwestern University · University of Freiburg · Friedrich-Alexander-Universität Erlangen-Nürnberg · University Medical Center Freiburg · Universitätsklinikum Erlangen · Robert H. Lurie Comprehensive Cancer Center of Northwestern University · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center – University of Freiburg , Freiburg ,
Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University , Chicago, Illinois ,
Department of Neurosurgery, Medical Center, University of Freiburg , Freiburg ,
Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Erlangen ,
Faculty of Medicine, Freiburg University , Freiburg ,
German Cancer Consortium (DKTK) , Partner Site Freiburg, Freiburg ,
Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg , Freiburg ,
Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center - University of Freiburg , 79106 Freiburg, Germany
Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center - University of Freiburg, 79106 Freiburg, Germany
Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center , Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Faculty of Medicine, Freiburg University, Germany
German Cancer Consortium (DKTK) , partner site Freiburg, Germany
Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg
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