Single-cell profiling of peripheral neuroblastic tumors identifies an aggressive transitional state that bridges an adrenergic-mesenchymal trajectory

Yuan, Xiaojun; Seneviratne, Janith A.; Du, Shibei; Xu, Ying; Chen, Yijun; Jin, Qianya; Jin, Xuanxuan; Balachandran, Anushree; Huang, Shixian; Xü, Yanli; Zhai, Yue; Lu, Liumei; Tang, Mengjie; Dong, Yushuang; Cheung, Belamy B.; Marshall, Glenn M.; Shi, Weixing; Carter, Daniel; Zhang, Chao

doi:10.1016/j.celrep.2022.111455

Cited by 22 publications

(18 citation statements)

References 66 publications

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“…We also propose that several SOX11 driven functions are co-opted by the transformed neuroblasts contributing to the aggressive phenotype of high-risk adrenergic NBs. Further support for this view comes from the recent description of a unique aggressive transitional cell state important for the inter-transition between adrenergic and mesenchymal cells through single-cell RNA-sequencing analysis of peripheral neuroblastic tumors 26 . Interestingly, SOX11 is described as a marker gene of the transitional state, amongst MYCN and others, while GATA3 and HAND2 mark the adrenergic state.…”

Section: Discussionmentioning

confidence: 98%

SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry

et al. 2023

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The pediatric extra-cranial tumor neuroblastoma displays a low mutational burden while recurrent copy number alterations are present in most high-risk cases. Here, we identify SOX11 as a dependency transcription factor in adrenergic neuroblastoma based on recurrent chromosome 2p focal gains and amplifications, specific expression in the normal sympatho-adrenal lineage and adrenergic neuroblastoma, regulation by multiple adrenergic specific (super-)enhancers and strong dependency on high SOX11 expression in adrenergic neuroblastomas. SOX11 regulated direct targets include genes implicated in epigenetic control, cytoskeleton and neurodevelopment. Most notably, SOX11 controls chromatin regulatory complexes, including 10 SWI/SNF core components among which SMARCC1, SMARCA4/BRG1 and ARID1A. Additionally, the histone deacetylase HDAC2, PRC1 complex component CBX2, chromatin-modifying enzyme KDM1A/LSD1 and pioneer factor c-MYB are regulated by SOX11. Finally, SOX11 is identified as a core transcription factor of the core regulatory circuitry (CRC) in adrenergic high-risk neuroblastoma with a potential role as epigenetic master regulator upstream of the CRC.

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Section: Discussionmentioning

confidence: 98%

SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry

et al. 2023

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“…Intermediate or transition cellular states are widely induced in tumors. For instance, in human melanoma 34 , a transitional CD8 state is observed, and in peripheral neuroblastic tumors, an intermediate state is observed between adrenergic and mesenchymal neuroblasts 35 . To find the cells with intermediate states, LiverCT can also calculated an “intermediate” score for query cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

uniLIVER: a Human Liver Cell Atlas for Data-Driven Cellular State Mapping

Wu,

Fan,

Miao

et al. 2023

Preprint

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The liver performs several vital functions such as metabolism, toxin removal and glucose storage through the coordination of various cell types. The cell type compositions and cellular states undergo significant changes in abnormal conditions such as fatty liver, cirrhosis and liver cancer. As the recent breakthrough of the single-cell/single-nucleus RNA-seq (sc/snRNA-seq) techniques, there is a great opportunity to establish a reference cell map of liver at single cell resolution with transcriptome-wise features. In this study, we build a unified liver cell atlas uniLIVER by integrative analyzing a large-scale sc/snRNA-seq data collection of normal human liver with 331,125 cells and 79 samples from 6 datasets. Besides the hierarchical cell type annotations, uniLIVER also proposed a novel data-driven strategy to map any query dataset to the normal reference map by developing a machine learning based framework named LiverCT. Applying LiverCT on the datasets from multiple abnormal conditions (1,867,641 cells and 439 samples from 12 datasets), the alterations of cell type compositions and cellular states were systematically investigated in liver cancer.

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“…In addition, scRNA-seq often falls short in identifying transient fluctuations from the transcriptional changes of biological meaning. The latter require some level of epigenetic memory to convey biological meaning and we hypothesise these underpin plasticity-first evolution [10][11][12][13][14][15]20,[39][40][41] . Our study addresses these challenges through an in-depth exploration of the relationship between cell states and treatment effects by combining evolutionary experimental approaches with integrated DNA barcodes readable on DNA and scRNA-seq platforms.…”

Section: Discussionmentioning

confidence: 99%

“…Initial experiments identified plasticity, transitioning from ADRN to undifferentiated and resistant MES phenotypes during therapy in vitro. Significantly, while the presence of MES-like gene signatures has been reported in a minor subset of peripheral neuroblastic tumours and PDX mouse models 19,20 , recent data show the ADRN profile is predominant in metastatic neuroblastoma 21 . Further studies are therefore needed to decode phenotypic transition types and principles, and investigate their evolutionary relevance.…”

Section: Introductionmentioning

confidence: 98%

Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma

Roux,

Hamer,

Shea

et al. 2023

Preprint

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In paediatric cancers like neuroblastoma, limited genetic diversity emphasizes the role of phenotypic heterogeneity in driving malignancy. We investigated this phenomenon using experimental evolution and single-cell techniques in neuroblastoma preclinical models. Our findings reveal that neuroblastoma cells navigate multistable phenotypic landscapes, named plasticity systems. These finely regulate their topology and dynamics enabling tolerance, persistence, and regrowth in response to treatment. While preferential killing of adrenergic cells (ADRN), notably under cisplatin treatment, enriches drug-tolerant persister (DTP) populations with mesenchymal (MES) properties, we also observed phenotypic transitions contributing to DTP entry and exit. Additionally, single-cell-derived clone experiments unveiled a spectrum of heritable plasticity traits linked to functional properties, influencing DTP behaviour. Mathematical modelling supports the critical role of all cell phenotypes in evolutionary adaptation. Collectively, our study depicts plasticity systems as key early cancer drivers of adaptive evolution in neuroblastoma through regulating the multistability and dynamics of phenotypic landscapes. These insights underscore the necessity of decoding plasticity for advancing long-term therapeutic effectiveness.

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Single-cell profiling of peripheral neuroblastic tumors identifies an aggressive transitional state that bridges an adrenergic-mesenchymal trajectory

Cited by 22 publications

References 66 publications

SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry

SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry

uniLIVER: a Human Liver Cell Atlas for Data-Driven Cellular State Mapping

Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma

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