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Neuroblastoma tumor heterogeneity and cell plasticity (from PDX and cell lines)

ABSTRACT: Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific core regulatory circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain to be defined. Here, we demonstrate that GATA3 but not PHOX2A or PHOX2B knock-out in noradrenergic cells induces a mesenchymal phenotype. We further document a spontaneous plasticity between the noradrenergic and mesenchymal identities in a subset of cell lines and identify transcription factors expressed in transition cells between the two states. Strikingly, mesenchymal neuroblastoma cells revert to a noradrenergic phenotype in vivo. Consistently, tumor cells with a mesenchymal identity are not detected in single-cell transcriptomic analyses of neuroblastoma tumors and PDX models. Our data also highlight neuroblastoma intra-tumor heterogeneity with the co-existence of distinct tumor populations, including sympathoblast-like and chromaffin-like cells suggesting that neuroblastoma cells arise from a common sympatho-adrenal progenitor.

PROVIDER: EGAS00001004781 | EGA |

REPOSITORIES: EGA

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Neuroblastoma tumor heterogeneity and cell plasticity (from patients)

Project description:Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific core regulatory circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain to be defined. Here, we demonstrate that GATA3 but not PHOX2A or PHOX2B knock-out in noradrenergic cells induces a mesenchymal phenotype. We further document a spontaneous plasticity between the noradrenergic and mesenchymal identities in a subset of cell lines and identify transcription factors expressed in transition cells between the two states. Strikingly, mesenchymal neuroblastoma cells revert to a noradrenergic phenotype in vivo. Consistently, tumor cells with a mesenchymal identity are not detected in single-cell transcriptomic analyses of neuroblastoma tumors and PDX models. Our data also highlight neuroblastoma intra-tumor heterogeneity with the co-existence of distinct tumor populations, including sympathoblast-like and chromaffin-like cells suggesting that neuroblastoma cells arise from a common sympatho-adrenal progenitor.

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Cell plasticity in neuroblastoma

Project description:Two cell identities, noradrenergic and mesenchymal, have been characterized in neuroblastoma cell lines according to their epigenetic landscapes relying on specific circuitries of transcription factors. Yet, their relationship and relative contribution in patient tumors remain poorly defined. Our results now document spontaneous plasticity in several neuroblastoma models between noradrenergic and mesenchymal tumor states and show that this plasticity is reversible and relies on epigenetic reprogramming. We demonstrate that an in vivo microenvironment provides a powerful pressure towards a noradrenergic identity for these models. Interestingly, single-cell RNA-seq analyses of 18 tumor biopsies and 15 PDX models revealed that tumor cells systematically exhibit a noradrenergic identity. Yet, our data highlight a population of noradrenergic tumor cells with mesenchymal features, demonstrating that the plasticity described in cellular models between both identities is relevant in neuroblastoma patients. Our work also emphasizes that both external cues of the environment and intrinsic factors influence plasticity and cell identity in neuroblastoma.

2023-03-27 | GSE154907 | GEO

Mesenchymal differentiation of neuroblastoma cell lines

Project description:Mesenchymal differentiation of neuroblastoma cell lines

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Expression profiles of pediatric solid tumor cell lines

Project description:For identification of candidate genes that is specifically expressed in Ewing family tumor (EFT) cells, we performed DNA microarray-based global expression profiling using Affymetrix Human Genome U133 Plus 2.0 Array and analyxed expression profiles from EFT cell lines (7 lines), neuroblastoma (NB) cell lines (3 lines), a Rhabdomyosarcoma (RMS) cell line, and a human immortalized mesenchymal progenitor cells UET-13 cells. Keywords: Ewing family tumor

2007-07-27 | GSE8596 | GEO

Transcription profiling of human pediatric solid tumor cell lines

2008-06-16 | E-GEOD-8596 | biostudies-arrayexpress

Epigenetic state determines inflammatory sensing in neuroblastoma [RNA-seq]

Project description:Immunotherapy has revolutionized cancer treatment, but many cancers are not impacted by currently available immunotherapeutic strategies. Here, we investigated inflammatory signaling pathways in neuroblastoma, a classically “cold” pediatric cancer. By testing the functional response of a panel of 20 diverse neuroblastoma cell lines to three different inflammatory stimuli, we found that all cell lines have intact interferon signaling and all but one lack functional cytosolic DNA sensing via cGAS-STING. However, dsRNA sensing via TLR3 was heterogeneous, as was signaling through other dsRNA sensors and TLRs more broadly. Seven cell lines showed robust response to dsRNA, six of which are in the mesenchymal epigenetic state, while all unresponsive cell lines are in the adrenergic state. Genetically switching adrenergic cell lines towards the mesenchymal state fully restored responsiveness. In responsive cells, dsRNA sensing results in the secretion of pro-inflammatory cytokines, enrichment of inflammatory transcriptomic signatures, and increased tumor killing by T cells in vitro. Using single cell RNA sequencing data, we show that human neuroblastoma cells with stronger mesenchymal signatures have a higher basal inflammatory state, demonstrating intra tumoral heterogeneity in inflammatory signaling that has significant implications for immunotherapeutic strategies in this aggressive childhood cancer.

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Epigenetic state determines inflammatory sensing in neuroblastoma [ATAC-seq]

2022-01-22 | GSE182041 | GEO

Genome-wide analysis of parental wild-type and derived doxorubicin resistant SK-N-SH neuroblastoma cell lines as well as those co-treated with the histone deacetylase inhibitor SAHA

Project description:Analysis of varied biologic pathways in neuroblastoma SK-N-SH cells grown in doxorubicin and/or SAHA. The hypothesis was that SK-N-SH cells undergo a mesenchymal change through mesenchymal change resulting in a more invasive as well as drug resistant phenotype, and that the mechanism of SAHAs effect on drug resistance may be revealed through this analysis. Total RNA was isolated from wild type, SAHA treated wild type cells, doxorubicin resistant, and SAHA treated doxorubicin resistant SK-N-SH cell lines in triplicate.

2016-05-31 | E-GEOD-47668 | biostudies-arrayexpress

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

Project description: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 cells from 10 PNTs demonstrated extensive transcriptomic heterogeneity. Examination of PNT microenvironments showed 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. 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.

2022-10-04 | GSE192906 | GEO

Neuroblastoma is composed of two super enhancer-associated differentiation states

Project description:Intra-tumour heterogeneity is increasingly appreciated as a determinant of tumour recurrence. Several tumour types were recently found to include phenotypically divergent cell types, reflecting lineage development stages (1,2,3). Lineage identity has been proposed to ensue super-enhancer (SE)-associated transcription factor (TF) networks (4,5), but their role in intra-tumour heterogeneity is unknown. Neuroblastoma is a paediatric tumour of the adrenergic differentiation lineage. Here we show that most neuroblastoma tumors include two types of tumor cells with highly diverging gene expression profiles. The undifferentiated mesenchymal cells and more differentiated adrenergic cells can interconvert and may relate to normal lineage differentiation stages. ChIP-seq analysis of isogenic pairs of mesenchymal and adrenergic neuroblastoma cells revealed a distinct, highly consistent super-enhancer landscape for each cell type. Two SE-associated TF networks emerged that potentially master each cell type. Accordingly, the mesenchymal TF PRRX1 could reprogram the SE- and mRNA-profiles of adrenergic cells towards a mesenchymal state. To assess the clinical relevance of this bi-phasic system, we investigated chemo-sensitivity of both cell types. Mesenchymal cells were more resistant in vitro and were enriched in post-therapy and relapsed neuroblastoma in patients. Intra-tumor heterogeneity in neuroblastoma is therefore structured according to distinct SE-associated transcriptional programs that mediate a dynamic bi-phasic structure.

2017-05-19 | GSE91028 | GEO

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