Single-Cell Characterization of Malignant Phenotypes and Developmental Trajectories of Adrenal Neuroblastoma

Dong, Rui; Yang, Ran; Zhan, Yong; Lai, Huadong; Ye, Chunjing; Yao, Xiaoying; Luo, Wenqin; Cheng, Xiaomu; Miao, Juju; Wang, Junfeng; Liu, Bai-Hui; Liu, Xiangqi; Xie, Lulu; Li, Yang; Zhang, Man; Lian, Chen; Song, Weichen; Qian, Wei; Gao, Wei‐Qiang; Tang, Yiqun; Shen, Chunyan; Jiang, Wei; Chen, Gong; Yao, Wei; Xiao, Xianmin; Zheng, Shan; Li, Kai; Wang, Jia

doi:10.1016/j.ccell.2020.08.014

Cited by 158 publications

(223 citation statements)

References 79 publications

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“…Altogether, our data obtained on a variety of cellular models and PDXs provide a biological explanation for the absence of mesenchymal tumor cells in vivo . This observation is also in line with the very recent study performed by Dong and colleagues that identified normal, but not tumor, mesenchymal cells in adrenal neuroblastoma tumors by single-cell RNA sequencing 33 . Interactions between tumor cells and several cell populations of the microenvironment may influence the tumor cell phenotype and play a role in tumor progression, as previously demonstrated for tumor-associated inflammatory cells 34 .…”

Section: Discussionsupporting

confidence: 90%

“…Recently, this hierarchical dogma of normal differentiation has been questioned with the identification of a population of Schwann cell precursors (SCPs) as the main reservoir of adrenal chromaffin cells in the mouse 26 . In their recent paper, Dong et al who analyzed human fetal adrenal gland at the single-cell level, in addition to adrenal neuroblastoma tumors, concluded that malignant cells had a predominant chromaffin-cell-like phenotype 33 . We nevertheless disagree with their interpretation of cell phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Interplay between intrinsic reprogramming potential and microenvironment controls neuroblastoma cell plasticity and identity

Thirant

Peltier

Durand

et al. 2021

Preprint

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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. Here, we demonstrate that the knock-out of GATA3, but not of PHOX2A or PHOX2B, in noradrenergic cells induces a mesenchymal phenotype. Our results document spontaneous plasticity in several models between both identities and show that plasticity relies on epigenetic reprogramming. We demonstrate that an in vivo microenvironment provides a powerful pressure towards a noradrenergic identity for these models. Consistently, tumor cells with a mesenchymal identity are not detected in a series of PDX models. Further study of the intra-tumor noradrenergic heterogeneity reveals two distinct cell populations exhibiting features of chromaffin-like or sympathoblast-like cells. This work emphasizes that both external cues of the environment and intrinsic factors control plasticity and cell identity in neuroblastoma.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Interplay between intrinsic reprogramming potential and microenvironment controls neuroblastoma cell plasticity and identity

Thirant

Peltier

Durand

et al. 2021

Preprint

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“…Further, cell clusters were identified, and their transcriptomes were cross-compared with those of cell clusters obtained from healthy tissue where the malignancy is commonly detected, specifically with human (n=3) and mouse (n=5) post-natal adrenal glands. For this comparison we also included recently published single-cell sequencing datasets from 10X single-sequenced NB tumors (n=8) [13], E12-E13 embryonic mouse adrenal anlagen [6], human fetal adrenal gland [14], and the transcriptional profiles of neuroblastoma mesenchymal-/NCC-like and (nor-)adrenergic cell lineages [15,16]. We identified a cluster of TRKB+ cholinergic cells in the human post-natal adrenal gland, that differ from previously described embryonic Schwann cell precursors (SCP).…”

Section: Introductionmentioning

confidence: 99%

Single-nuclei transcriptomes from human adrenal gland reveals distinct cellular identities of low and high-risk neuroblastoma tumors

Bedoya-Reina

Arceo

et al. 2021

Preprint

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Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. We studied single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compared tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles an unknown subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations revealed different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.

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“…We attempted to systematically review current efforts to differentiate neuroblastoma directly targeting the classical retinoic acid pathway and indirectly by mimicking their downstream effects of RA published from 1 January 1980 to 1 July 2020. The complexity of neuroblastoma biology makes it difficult to identify intercellular signals that could be either disrupted or induced, to drive tumour cells towards differentiation [72,93,94]. Similarly, signalling interactions between different components of the tumour microenvironment and their interactions with the tumour cells themselves remain poorly characterized, despite numerous focused efforts [95,96].…”

Section: Discussionmentioning

confidence: 99%

Differentiating Neuroblastoma: A Systematic Review of the Retinoic Acid, Its Derivatives, and Synergistic Interactions

Bayeva¹,

Coll²,

Piskareva

2021

JPM

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A neuroblastoma (NB) is a solid paediatric tumour arising from undifferentiated neuronal cells. Despite the recent advances in disease management and treatment, it remains one of the leading causes of childhood cancer deaths, thereby necessitating the development of new therapeutic agents and regimens. Retinoic acid (RA), a vitamin A derivative, is a promising agent that can induce differentiation in NB cells. Its isoform, 13-cis RA or isotretinoin, is used in NB therapy; however, its effectiveness is limited to treating a minimal residual disease as maintenance therapy. As such, research focuses on RA derivatives that might increase the anti-NB action or explores the potential synergy between RA and other classes of drugs, such as cellular processes mediators, epigenetic modifiers, and immune modulators. This review summarises the in vitro, in vivo, and clinical data of RA, its derivatives, and synergising compounds, thereby establishing the most promising RA derivatives and combinations of RA for further investigation.

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Single-Cell Characterization of Malignant Phenotypes and Developmental Trajectories of Adrenal Neuroblastoma

Cited by 158 publications

References 79 publications

Interplay between intrinsic reprogramming potential and microenvironment controls neuroblastoma cell plasticity and identity

Interplay between intrinsic reprogramming potential and microenvironment controls neuroblastoma cell plasticity and identity

Single-nuclei transcriptomes from human adrenal gland reveals distinct cellular identities of low and high-risk neuroblastoma tumors

Differentiating Neuroblastoma: A Systematic Review of the Retinoic Acid, Its Derivatives, and Synergistic Interactions

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