Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression

Rifatbegovic, Fikret; Frech, Christian; Abbasi, Mojtaba; Taschner‐Mandl, Sabine; Weiss, Tamara; Schmidt, Wolfgang M.; Schmidt, Iris; Ladenstein, Ruth; Ambros, Inge M.; Ambros, Peter F.

doi:10.1002/ijc.31053

Cited by 33 publications

(39 citation statements)

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“…Next, we evaluated whether either of the three cell states related to a metastatic phenotype. For this, we calculated a disseminated tumor cell (DTC) score for gene expression in each cell state by determining the difference between the expression of significantly up-regulated and down-regulated genes of a previously published DTC gene set 25 . Interestingly, the transitional malignant cells shared the highest similarity with DTCs from the bone marrow which is the most common distant metastatic site of neuroblastoma ( Supplementary Fig.…”

Section: Transitional Neuroblasts Are Defined By An Aggressive Neurodmentioning

confidence: 99%

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Yuan

Seneviratne

et al. 2020

Preprint

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Peripheral neuroblastic tumors (PNTs) are the most common extracranial solid tumors in early childhood.They represent a spectrum of neural crest derived tumors including neuroblastoma, ganglioneuroblastoma and ganglioneuroma. PNTs exhibit heterogeneity due to interconverting malignant cell states described as adrenergic/nor-adrenergic or mesenchymal/neural crest cell in origin. The factors determining individual patient levels of tumor heterogeneity, their impact on the malignant phenotype, and the presence of other cell states are unknown. Here, single-cell RNA-sequencing analysis of 4267 cells from 7 PNTs demonstrated extensive transcriptomic heterogeneity. Trajectory modelling showed that malignant neuroblasts move between adrenergic and mesenchymal cell states via a novel state that we termed a "transitional" phenotype. Transitional cells are characterized by gene expression programs linked to a sympathoadrenal development, and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature was highly predictive of poor prognosis when compared to adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identified a similar transitional H3K27-acetylation super-enhancer landscape, supporting the concept that PNTs have phenotypic plasticity and transdifferentiation capacity. Additionally, examination of PNT microenvironments, found that neuroblastomas contained low immune cell infiltration, high levels of non-inflammatory macrophages, and low cytotoxic T lymphocyte levels compared with more benign PNT subtypes. Modeling of cell-cell signaling in the tumor microenvironment predicted specific paracrine effects toward the various subtypes of malignant cells, suggesting further cell-extrinsic influences on malignant cell phenotype. Collectively, our study reveals the presence of a previously unrecognized transitional cell state with high malignant potential and an immune cell architecture which serve both as potential biomarkers and therapeutic targets.Introduction Peripheral neuroblastic tumors (PNTs) represent a spectrum of tumors derived from the neural crest and account up to 8-10% of all pediatric malignancies. A salient feature of PNTs is a heterogeneous clinical course ranging from spontaneous regression to persistent disease progression 1 . Histologically, PNTs comprise four variants, including neuroblastoma (NB), ganglioneuroblastoma nodular (GNBn), ganglioneuroblastoma intermixed (GNBi), and ganglioneuroma (GN) 1 . GN and GNBi are low-grade in nature and usually curable by surgical resection alone 2 . In contrast, the most common subtype; NB is often lethal. Despite intensive treatments, the long-term survival of high-risk NB is less than 50% 3 .Around half of high-risk patients relapse after initial treatment response, and salvage therapies for relapsed patients are rarely effective 1 . Moreover, genomics studies comparing longitudinal samples f...

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Section: Transitional Neuroblasts Are Defined By An Aggressive Neurodmentioning

confidence: 99%

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Yuan

Seneviratne

et al. 2020

Preprint

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“…The older dataset, GSE25624 [ 19 ], contained data from a total of 40 samples. Recently, a dataset containing expression data of BM resident cells from children with NB in comparison with expression data of BM-infiltrating NB cells (GSE 94035) [ 25 ] became available, but the lack of expression data of BM resident cells from healthy children made it unsuitable to answer our question.…”

Section: Discussionmentioning

confidence: 99%

miRNA expression profile of bone marrow resident cells from children with neuroblastoma is not significantly different from that of healthy children

et al. 2018

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The miRNA expression profiles of bone marrow resident cells from children with neuroblastoma were compared to that of healthy children. No significant difference was found between localized and metastatic neuroblastoma, or between children with neuroblastoma and healthy children. By considering the fold change we identified six miRNAs over-expressed by more than 150 fold in neuroblastoma. Validation confirmed miR-221 over-expression in BM resident cells from children with neuroblastoma, regardless of localized or metastatic disease.MiR-221 over-expression was unlikely derived from neuroblastoma primary tumors or from bone marrow-infiltrating metastatic cells, since neuroblastoma cells expressed lower or similar amount of miR-221 than BM cells, respectively.To get insight on the genes potentially regulated by miR-221 we merged the list of miR-221 potential targets with the genes under-expressed by BM resident cells from children with neuroblastoma, as compared with healthy children. In silico analysis demonstrated that none of the miR-221 target genes belonged to heme biosynthetic processes found altered in children with neuroblastoma, whereas two genes associated with mitochondria. However, the encoded proteins were not under-expressed in children with neuroblastoma, making unlikely that altered erythrocyte maturation in children with neuroblastoma was mediated by miR-221.In conclusion, miRNA expression profiles of BM resident cells from children with localized and metastatic neuroblastoma were similar to that of BM resident cells from healthy children. Moreover, miRNAs expressed by neuroblastoma primary tumors or by BM-infiltrating NB cells do not appear to be involved in mediating the functional defect of erythrocyte maturation recently observed in children with neuroblastoma.

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“…The generated data were bioinformatically analyzed together with our previously published transcriptomic data sets of human primary SCs (SC, n=5), human injured fascicle explants (SC-IN, n=3) and NB cell lines STA-NB-6 (in triplicates), STA-NB-7 and STA-NB-15 (NB-CL, n=3) , and diagnostic, untreated stage 4 NBs (NB-TU, n=15) (Rifatbegovic et al, 2018). Respective GEO identifiers can be found in S. (Hartley & Mullikin, 2015) and then aligned to the human genome hs37d5 (ftp://ftp.1000genomes.ebi.ac.uk/)…”

Section: Proliferation and Differentiation Facs Panelsmentioning

confidence: 99%

Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

Weiss

Taschner‐Mandl

Bileck

et al. 2020

Preprint

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The remarkable plasticity of Schwann cells (SCs) enables the acquisition of repair-specific functions essential for peripheral nerve regeneration. We hypothesized that this plastic potential is manifested in stromal SCs found within mostly benign-behaving peripheral neuroblastic tumors. To shed light on the cellular state and impact of stromal SCs, we performed transcriptome profiling of human ganglioneuromas and neuroblastomas, rich and poor in SC-stroma, respectively, as well as human injured nerves, rich in repair SCs. The results revealed a nerve repair-characteristic gene expression signature of stromal SCs. In turn, primary repair SCs had a pro-differentiating and anti-proliferative effect on aggressive neuroblastoma 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 neuroblastoma cell lines. This study indicates that stromal SCs underwent an adaptive response to neuroblastic tumor cells and exert repairassociated functions in the microenvironment resulting in a benign tumor development.Further, SC-derived factors, such as EGFL8, may be of therapeutic value for aggressive, SCstroma poor neuroblastomas. SYNOPSISIn order to investigate the nature of stromal Schwann cells in benign peripheral neuroblastic tumors (ganglioneuromas), we compared the cellular state of stromal Schwann cells with repair-associated Schwann cells emerging in peripheral nerves after injury. • Stromal Schwann cells in ganglioneuromas and repair Schwann cells in injured nervesshare the expression of nerve repair-associated genes.• Neuroblastoma cell lines, derived from high-risk metastatic peripheral neuroblastic tumors (neuroblastomas), respond to primary repair Schwann cells and their secretome with increased neuronal differentiation and reduced proliferation. • Stromal and repair Schwann cells express the matricellular protein EGFL8, which is capable to induce neuronal differentiation of neuroblastoma cell lines in recombinant form. Human Schwann Cell Plasticity Weiss, Taschner-Mandl et al Page 4 of 48 ABBREVIATIONS SC … Schwann cell NT … peripheral neuroblastic tumor NB … neuroblastoma GNB … ganglioneuroblatoma GN … ganglioneuroma RT … room temperature IF … immunofluorescence THE PAPER EXPLAINED ProblemIn response to peripheral nerve damage, Schwann cells (SCs) are able to transform into specialized repair cells essential for nerve cell regeneration. Our previous studies indicated that this reactive/adaptive potential of human SCs is not restricted to injured nerve cells but also emerges in response to peripheral neuroblastic tumor cells. The usually benign subtypes of peripheral neuroblastic tumors, i.e. ganglioneuroblastomas and ganglioneuromas, contain neuronal differentiating tumor cells and are pervaded by various portions of stromal SCs. Of note, the amount of stromal SCs correlates with a favorable tumor behavior and increased patient survival, whereas aggre...

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Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression

Cited by 33 publications

References 50 publications

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory

miRNA expression profile of bone marrow resident cells from children with neuroblastoma is not significantly different from that of healthy children

Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8

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