Adrenergic to mesenchymal fate switching of neuroblastoma occurs spontaneously in vivo resulting in differential tumorigenic potential

Lecca, Maria C.; Jonker, MA; Abdul, U. Kulsoom; Küçükosmanoğlu, Aslı; Wieringen, WN van; Westerman, A

doi:10.31083/j.jmcm.2018.04.4221

Cited by 4 publications

(5 citation statements)

References 18 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using single-cell sequencing, we could facilitate virtual microdissection of malignant cells and microenvironmental heterogeneity within and between tumors. In particular, among malignant populations, we detected the expression of genes related to mesenchymal/neural crest cell and adrenergic/noradrenergic neuroblastoma cells, consistent with previous reports 7,8,36,37 . Notably however, we found that some high-risk tumors display an additional transitional state with gene expression characteristics associated with aggressive disease, rapid proliferation and metastasis.…”

Section: Discussionsupporting

confidence: 90%

“…Prior studies have speculated that adrenergic/noradrenergic cells transdifferentiate to mesenchymal/neural crest cells and vice versa 7,8,36,37,41 . This theory was primarily based on spontaneous state polarization of isogenic pairs of cells and forced overexpression experiments using strong lineage associated transcription factors to reprogram cell phenotype such as PHOX2B, PRRX1, ASCL1 and NOTCH3 7,8,36,41 .…”

Section: Pntsmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Pntsmentioning

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

View full text Add to dashboard Cite

show abstract

“…Single-cell subclones established from NB cell lines could repopulate both cellstates in vitro, indicating reversible dynamic transitions. Such spontaneous stochastic bidirectional interconversion was also seen in vivo (Lecca et al, 2018;Thirant et al, 2023;. Therefore, analogous to the well-studied phenomenon of epithelial-mesenchymal transition (EMT) and its reverse mesenchymal-epithelial transition (MET) (Kahlert et al, 2017;Lourenco et al, 2020;Pastushenko and Blanpain, 2019), neuroblastoma displays phenotypic transitions between the NOR and MES phenotypes -noradrenergic-mesenchymal transition (NMT) and mesenchymal-noradrenergic transition (MNT) (Figure 1).…”

Section: Introductionmentioning

confidence: 77%

Mutually exclusive teams-like patterns of gene regulation characterize phenotypic heterogeneity along the noradrenergic-mesenchymal axis in neuroblastoma

Sehgal,

Nayak,

Sahoo

et al. 2023

Preprint

View full text Add to dashboard Cite

Neuroblastoma is the most frequent extracranial pediatric tumor and leads to 15% of all cancer-related deaths in children. Tumor relapse and therapy resistance in neuroblastoma are driven by phenotypic plasticity and heterogeneity between noradrenergic (NOR) and mesenchymal (MES) cell states. Despite the importance of this phenotypic plasticity, however, the dynamics and molecular patterns associated with these bidirectional cell-state transitions remain relatively poorly understood. Here, we analyze multiple RNA-seq datasets at both bulk and single-cell resolution, to understand the association between NOR- and MES-specific factors. We observed that NOR-specific and MES-specific expression patterns are largely mutually exclusive, exhibiting a 'teams-like' behavior among the genes involved, reminiscent of our earlier observations in lung cancer and melanoma. This antagonism was noticed also in the association of NOR and MES phenotypes with metabolic reprogramming and with immunotherapy targets PD-L1 and GD2, and in experimental perturbations driving the NOR-MES and/or MES-NOR transition. Further, this 'teams-like' patterns was seen only among the NOR- and MES-specific genes, but not in housekeeping genes, possibly highlighting a hallmark of network topology enabling cancer cell plasticity.

show abstract

“…Transdifferentiation between these cell identities is associated with cellular plasticity ( van Groningen et al, 2017 ; van Groningen et al, 2019 ). The differentiation state of cells within a tumor and the cross-talk between the different subtypes is relevant in drug resistance and relapse ( Yan et al, 2011 ; Lecca et al, 2018 ). The differential responses to retinoic acid treatment and withdrawal we observed may also reflect these divergent differentiation states.…”

Section: Discussionmentioning

confidence: 99%

Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells

Gomez

Woods²,

Ramachandran³

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Neuroblastoma is a pediatric tumour that accounts for more than 15% of cancer-related deaths in children. High-risk tumours are often difficult to treat, and patients’ survival chances are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumours differentiate in response to retinoic acid. Within neuroblastoma tumors, two phenotypically distinct cell types have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries: adrenergic (ADRN) and mesenchymal (MES). We hypothesized that the distinct super-enhancers in these different tumour cells mediate differential response to retinoic acid. To this end, three different neuroblastoma cell lines, ADRN (MYCN amplified and non-amplified) and MES cells, were treated with retinoic acid, and changes in the super-enhancer landscape upon treatment and after subsequent removal of retinoic acid was studied. Using ChIP-seq for the active histone mark H3K27ac, paired with RNA-seq, we compared the super-enhancer landscape in cells that undergo neuronal differentiation in response to retinoic acid versus those that fail to differentiate and identified unique super-enhancers associated with neuronal differentiation. Among the ADRN cells that respond to treatment, MYCN-amplified cells remain differentiated upon removal of retinoic acid, whereas MYCN non-amplified cells revert to an undifferentiated state, allowing for the identification of super-enhancers responsible for maintaining differentiation. This study identifies key super-enhancers that are crucial for retinoic acid-mediated differentiation.

show abstract

Adrenergic to mesenchymal fate switching of neuroblastoma occurs spontaneously in vivo resulting in differential tumorigenic potential

Cited by 4 publications

References 18 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

Mutually exclusive teams-like patterns of gene regulation characterize phenotypic heterogeneity along the noradrenergic-mesenchymal axis in neuroblastoma

Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells

Contact Info

Product

Resources

About