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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182051 | GEO | 2022/01/22

REPOSITORIES: GEO

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Epigenetic state determines inflammatory sensing in neuroblastoma [ATAC-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.

2022-01-22 | GSE182041 | GEO

Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [ChIP-Seq]

Project description:GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells. Immunotherapy with anti-GD2 antibodies has revolutionized the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse and little is known about mechanisms of resistance to anti-GD2. Neuroblastomas harbor intrinsic transcriptional plasticity by co-opting divergent lineage-specific developmental programs between adrenergic and mesenchymal cell states. We found that reduced GD2 expression was significantly correlated with the adrenergic cell state in neuroblastoma and that an Adrenergic-to-Mesenchymal Transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Induced reprogramming of adrenergic cells with the master AMT regulator PRRX1 was sufficient to promote transcriptional rewiring in isogenic models and downregulate GD2 expression. Mechanistically, low-GD2 expressing cell lines demonstrate significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Primary neuroblastoma tumors enriched for mesenchymal features show demonstrably lower GD3 synthase expression as compared to adrenergic tumors. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to an anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.

2022-04-26 | GSE196861 | GEO

Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [RNA-seq SKNBE2 or KPNYN]

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Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [RNA-seq kelly cells]

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Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [RNA-seq SK-N-AS]

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Epigenetic reversal of lineage plasticity enhances responsiveness to anti-GD2 therapy in neuroblastoma [ATAC-seq SK-N-AS]

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Epigenetic state determines inflammatory sensing in neuroblastoma

Project description:Epigenetic state determines inflammatory sensing in neuroblastoma

| PRJNA754370 | ENA

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses (ATAC-seq)

Project description:Mesenchymal tumor subclones secrete cytokines that promote tumorigenesis and chemoresistance, but the mechanism that underlies this phenomenon remains poorly understood. Here we identify a de-repressed subclass of endogenous retroviruses (ERVs) that engage innate immune signaling in mesenchymal cancer cells. These Stimulated 3 Prime Antisense Retroviral Coding Sequences (SPARCS) are oriented inversely in 3’UTRs of certain interferon-inducible genes, generating dsRNA following IFN exposure. Sensing of this dsRNA by MAVS fuels activation of TBK1, IRF3, and STAT1 signaling. SPARCS induction in human tumors is tightly associated with B2M and MHC class 1 antigen expression, mesenchymal markers, and downregulation of chromatin modifying enzymes. Cell lines poised to induce high levels of SPARCS expression are associated with an AXL positive mesenchymal cell state. These data unveil a novel subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer.

2019-10-15 | GSE114864 | GEO

Genetic Predisposition to Neuroblastoma Results from a Regulatory Polymorphism that Promotes the Adrenergic Cell State

Project description:Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like “mesenchymal” cell state and a more differentiated sympathetic “adrenergic” cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional co-factor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism G/T that affects a GATA motif in the first intron of LMO1. Here we showed that wild-type zebrafish with the GATA genotype developed adrenergic neuroblastoma, while knock-in of the protective TATA allele at this locus reduced the penetrance of MYCN-driven tumors, which were restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrated that TATA/TATA tumors also exhibited a mesenchymal cell state and were low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduced the neuroblastoma initiation rate by preventing formation of the adrenergic cell state, a mechanism that was conserved over 400 million years of evolution separating zebrafish and humans.

2023-04-25 | GSE224158 | GEO

Neuroblastoma is composed of two super enhancer-associated differentiation states [ChIP-seq]

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.

2021-10-01 | GSE126054 | GEO

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