Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma

Jansky, Selina; Sharma, Ashwini Kumar; Körber, Verena; Quintero, Andrés; Toprak, Umut; Wecht, Elisa M; Gartlgruber, Moritz; Greco, Alessandro; Chomsky, Elad; Grünewald, Thomas G.P.; Henrich, Kai-Oliver; Tanay, Amos; Herrmann, Carl; Höfer, Thomas; Westermann, Frank

doi:10.1038/s41588-021-00806-1

Cited by 152 publications

(254 citation statements)

References 78 publications

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“…Additionally, overexpression of Cyclin D1, a binding partner with CDK4/6, in neuroblasts and low Cyclin D1 expression in ganglioneuroma indicate an involvement of dysregulation of the G1 cell cycle checkpoint in neuroblastic tumor differentiation [ 6 ]. The recent advances in single-cell transcriptomic analyses showed that expression of CCND1, which encodes Cyclin D1, was specific in the neuroblast lineage, whereas expression of the cell cycle inhibitor CDKN1C was specific to chromaffin cells, supporting the importance of Cyclin D1 in developmental trajectories of the peripheral neuroblastic tumors [ 101 ]. Altogether, although the direct link between the degree of differentiation in these tumors and possible molecular targeting therapies has been less characterized, the dysregulation of the G1 cell cycle checkpoint may implicate beneficial therapeutic effects by putting the “brakes” on the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Ando

Nakagawara

2021

Biomolecules

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Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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Section: Discussionmentioning

confidence: 99%

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Ando

Nakagawara

2021

Biomolecules

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“…Neuroblastomas in patients and experimental cell lines generally possess one of two CRC modules – the immature neural crest-like or mesenchymal subtype, defined by high expression levels of the PRRX1, YAP/TAZ and AP-1 transcription factor genes, or the more commonly observed adrenergic CRC, characterized by high expression levels of HAND2, ISL1, PHOX2B, GATA3, TBX2 , and ASCL1 ( 12–14 ). Current models suggest that the neural crest-derived progenitors normally give rise to committed progenitors with the adrenergic cell state, culminating in terminally differentiated sympathetic neuronal cells and chromaffin neuroendocrine cells of the peripheral sympathetic nervous system ( 15, 16 ). In neuroblastomas with MYCN amplification, this oncogene stabilizes the adrenergic CRC to drive the expression of its transcriptional regulatory network and enforce an immature neuroblast cell state, while suppressing developmental signals that would normally induce differentiation or senescence ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid rewires the adrenergic core regulatory circuitry of childhood neuroblastoma

Zimmerman

Durbin

et al. 2020

Preprint

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Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation in both primary neuroblastomas and cell lines; however, the underlying mechanisms remain unclear. Here we show that when MYCN-amplified neuroblastomas cells are treated with all-trans retinoic acid (ATRA), histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1, HIC1 and SOX4 expression. These findings indicate that treatment with ATRA can reprogram the enhancer landscape to collapse the adrenergic CRC, resulting in downregulation of MYCN expression, while upregulating a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids against high-risk neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of gene amplification.

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“…In total, 24 overlapping genes could be retrieved, with high expression of 15 of those significantly correlating to poor overall patient survival in human primary neuroblastoma ( Figure 5 A, left, GSE45547, n = 649). Single-cell RNA-seq data of the sympathoadrenal lineage and adrenal medulla respectively indicate that CDCA8 displays nearly exclusive strong expression in the proliferating sympathoblasts [ 49 ] and cycling neuroblast population [ 50 ] ( Figure 5 B).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to ALK and ASCL1 that were previously reported in the context of neuroblastoma, a novel interesting candidate gene “Claspin” ( Clspn ) was identified, for which recently a critical role was described in protection of cancer cells from replication stress and which has been reported as a key gene in normal developmental controlled gene amplification in Drosophila [ 67 ]. Single-cell RNA-seq data of the sympathoadrenal lineage and adrenal medulla respectively indicate that CLSPN displays nearly exclusive strong expression in the proliferating sympathoblasts [ 49 ] and cycling neuroblast population [ 50 ] ( Figure 5 D, bottom) We also evaluated the overlap of the set of significantly upregulated genes in the course of murine TH-MYCN-driven neuroblastoma tumor development with the neuroblastoma specific dependencies as defined by the recent pediatric cancer dependency map from Dharia et al [ 68 ]. When again only considering those genes that also significantly correlate with a poor overall neuroblastoma patient survival, we identified 11 additional candidate dependency genes that were significantly differentially expressed (absolute log 2 fold change threshold of 1 and adjusted p < 0.01) between TH-MYCN +/+ and wild-type mice exclusively at Week 6 compared to Week 1 ( AGBL5 , ATAD5 , CHEK1 , HDX , NEDD1 , PABPC1 , PHF19 , POLD1 , PYCR1 , SMC2 and WNT5B ) that were not identified as “MYCN-amplified/neuroblastoma” specific dependencies by the Avana CRISPR screen from the Depmap initiative.…”

Section: Resultsmentioning

confidence: 99%

MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation

Wyn

Zimmerman

Weichert-Leahey

et al. 2021

Cancers

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Roughly half of all high-risk neuroblastoma patients present with MYCN amplification. The molecular consequences of MYCN overexpression in this aggressive pediatric tumor have been studied for decades, but thus far, our understanding of the early initiating steps of MYCN-driven tumor formation is still enigmatic. We performed a detailed transcriptome landscaping during murine TH-MYCN-driven neuroblastoma tumor formation at different time points. The neuroblastoma dependency factor MEIS2, together with ASCL1, was identified as a candidate tumor-initiating factor and shown to be a novel core regulatory circuit member in adrenergic neuroblastomas. Of further interest, we found a KEOPS complex member (gm6890), implicated in homologous double-strand break repair and telomere maintenance, to be strongly upregulated during tumor formation, as well as the checkpoint adaptor Claspin (CLSPN) and three chromosome 17q loci CBX2, GJC1 and LIMD2. Finally, cross-species master regulator analysis identified FOXM1, together with additional hubs controlling transcriptome profiles of MYCN-driven neuroblastoma. In conclusion, time-resolved transcriptome analysis of early hyperplastic lesions and full-blown MYCN-driven neuroblastomas yielded novel components implicated in both tumor initiation and maintenance, providing putative novel drug targets for MYCN-driven neuroblastoma.

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Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma

Cited by 152 publications

References 78 publications

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Retinoic acid rewires the adrenergic core regulatory circuitry of childhood neuroblastoma

MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation

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