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Schwann cell plasticity regulates neuroblastic tumor cell differentiation

ABSTRACT: The remarkable plasticity of Schwann cells (SCs) is essential for nerve regeneration but also contributes to neuropathies and cancer progression. It has not yet been investigated whether the adaptive potential of SCs is manifested in stromal, tumor associated SCs characteristically found within a benign subtype of neuroblastic tumors (NBTs). We here performed transcriptome profiling of human NBTs, rich and poor in SC stroma, as well as human injured nerves, rich in repair SCs, revealing that stromal SCs exhibit a repair SC characteristic gene expression signature. In turn, primary repair SCs had a pro-differentiating and anti-proliferative effect on NBT cell lines after direct and trans-well co-culture. Within the pool of secreted stromal/repair SC factors, we identified EGFL8, a matricellular protein with so far undescribed function, to induce neuronal differentiation of aggressive NBT cells. EGFL8 expression further correlated with favorable tumor stage and increased patient survival. Our findings suggest that stromal SCs exert nerve repair associated functions in the tumor-environment and underline the therapeutic value of SC-derived factors for aggressive, SC stroma-poor NBTs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147635 | GEO | 2020/12/23

REPOSITORIES: GEO

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Schwann cell plasticity regulates neuroblastic tumor cell differentiation

Project description:The remarkable plasticity of Schwann cells (SCs) is essential for nerve regeneration but also contributes to neuropathies and cancer progression. It has not yet been investigated whether the adaptive potential of SCs is manifested in stromal, tumor associated SCs characteristically found within a benign subtype of neuroblastic tumors (NBTs). We here performed transcriptome profiling of human NBTs, rich and poor in SC stroma, as well as human injured nerves, rich in repair SCs, revealing that stromal SCs exhibit a repair SC characteristic gene expression signature. In turn, primary repair SCs had a pro-differentiating and anti-proliferative effect on NBT cell lines after direct and trans-well co-culture. Within the pool of secreted stromal/repair SC factors, we identified EGFL8, a matricellular protein with so far undescribed function, to induce neuronal differentiation of aggressive NBT cells. EGFL8 expression further correlated with favorable tumor stage and increased patient survival. Our findings suggest that stromal SCs exert nerve repair associated functions in the tumor-environment and underline the therapeutic value of SC-derived factors for aggressive, SC stroma-poor NBTs.

2021-01-13 | PXD018267 | Pride

Schwann cell plasticity regulates neuroblastic tumor cell differentiation - phosphoproteomics

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Proteomics and transcriptomics of peripheral nerve tissue and cells unravel new aspects of the human Schwann cell repair phenotype

Project description:The remarkable feature of Schwann cells (SCs) to transform into a repair phenotype turned the spotlight on this powerful cell type. SCs provide the regenerative environment for axonal re-growth after peripheral nerve injury (PNI) and play a vital role in differentiation of neuroblastic tumors into a benign subtype of neuroblastoma, a tumor originating from neural crest-derived neuroblasts. Hence, understanding their mode-of-action is of utmost interest for new approaches in regenerative medicine, but also for neuroblastoma therapy. However, literature on human SCs is scarce and it is unknown to which extent human SC cultures reflect the SC repair phenotype developing after PNI in patients. We performed high-resolution proteome profiling and RNA-sequencing on highly enriched human SC and fibroblast cultures, control and ex vivo degenerated nerve explants to identify novel molecules and functional processes active in repair SCs. In fact, we found cultured SCs and degenerated nerves to share a similar repair SC-associated expression signature, including the upregulation of JUN, as well as two prominent functions, i.e., myelin debris clearance and antigen presentation via MHCII. In addition to myelin degradation, cultured SCs were capable of actively taking up cell-extrinsic components in functional phagocytosis and co-cultivation assays. Moreover, in cultured SCs and degenerated nerve tissue MHCII was upregulated at the cellular level along with high expression of chemoattractants and co-inhibitory rather than -stimulatory molecules. These results demonstrate human SC cultures to execute an inherent program of nerve repair and support two novel repair SC functions, debris clearance via phagocytosis-related mechanisms and type II immune-regulation.

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Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state [bulk RNA-seq]

Project description:Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to the pathogenesis of these tumors remains poorly understood. We performed scRNA-seq on 15 VS samples, with paired scATAC-seq (n=6) and exome sequencing (n=12). We identified diverse Schwann cell (SC), stromal, and immune populations in the VS TME and found that repair-like and MHC-II antigen presenting subtype SCs are associated with increased myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution of RNA-expression data from 195 tumors revealed Injury-like tumors are associated with larger tumor size, and scATAC-seq identified transcription factors associated with nerve repair among SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggested that SCs recruit monocytes. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be targeted to prevent tumor progression. This SubSeries is part of a SuperSeries (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE216784).

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Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state [RNA-seq-invitro]

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Disentangling glial diversity in peripheral nerves at single-nuclei resolution [bulk and RiboTag RNA-seq]

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Disentangling glial diversity in peripheral nerves at single-nuclei resolution [single-cell and single-nuclei RNA-seq]

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

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

2023-09-15 | GSE216782 | GEO

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

Project description:Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to the pathogenesis of these tumors remains poorly understood. We performed scRNA-seq on 15 VS samples, with paired scATAC-seq (n=6) and exome sequencing (n=12). We identified diverse Schwann cell (SC), stromal, and immune populations in the VS TME and found that repair-like and MHC-II antigen presenting subtype SCs are associated with increased myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution of RNA-expression data from 195 tumors revealed Injury-like tumors are associated with larger tumor size, and scATAC-seq identified transcription factors associated with nerve repair among SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggested that SCs recruit monocytes. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be targeted to prevent tumor progression. This SuperSeries is composed of the SubSeries listed below. Matching whole exome sequencing data is available via NCBI dbGaP (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA981645/).

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