Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma

Kerosuo, Laura; Neppala, Pushpa; Hsin, Jenny; Mohlin, Sofie; Vieceli, Felipe Monteleone; Torok, Zsofia; Laine, Antti; Westermarck, Jukka; Bronner, Marianne E.

doi:10.1073/pnas.1800039115

Cited by 40 publications

(35 citation statements)

References 70 publications

(91 reference statements)

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“…This suggests that either SK-N-BE(2)-C cells have retained early transcriptional plasticity, or more intriguingly, that NBs may arise prior to sympathoadrenal differentiation. This notion is supported by developmental experiments showing ectopic MYCN expression in the neural plate border resulting in a shift towards a CNS-like state (Kerosuo et al 2018) and the induction of NB in MYCN-overexpressing NCCs (Olsen et al 2017).…”

Section: Is Wnt Signalling a Major Determinant Of Nc And Nb Cell Fate?mentioning

confidence: 82%

“…This finding was confirmed and extended to show absence of MYCN expression in the condensed dorsal root and sympathetic ganglia. Elevating MYCN expression in the neural plate border was shown to lead to a change in neural crest identity, toward a more central nervous system fate (Kerosuo et al 2018). Transient overexpression of ectopic MYCN in early migrating cells, however, suggested that MYCN can regulate neural crest fate by regulating ventral migration and neuronal differentiation (Wakamatsu et al 1997).…”

Section: Differentiation Of the Neural Crest And Wnt Signallingmentioning

confidence: 99%

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Wnt signalling is a major determinant of neuroblastoma cell lineages

Szemes

Greenhough

Malik

2018

Preprint

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The neural crest, which has been referred to as the fourth germ layer, comprises a multipotent cell population which will specify diverse cells and tissues, including craniofacial cartilage and bones, melanocytes, the adrenal medulla and the peripheral nervous system. These cell fates are known to be determined by gene regulatory networks (GRNs) acting at various stages of neural crest development, such as induction, specification, and migration. Although transcription factor hierarchies and some of their interplay with morphogenetic signalling pathways have been characterised, the full complexity of activities required for regulated development remains uncharted. Deregulation of these pathways may contribute to tumourigenesis, as in the case of neuroblastoma, a frequently lethal embryonic cancer thought to arise from the sympathoadrenal lineage of the neural crest.In this conceptual analysis, we utilise next generation sequencing data from neuroblastoma cells and tumours to evaluate the possible influences of Wnt signalling on neural crest GRNs and on neuroblastoma cell lineages. We provide evidence that Wnt signalling is a major determinant of regulatory networks that underlie mesenchymal/NCClike cell identities through PRRX1 and YAP/TAZ transcription factors. Furthermore, Wnt may also co-operate with Hedgehog signalling in driving proneural differentiation programmes along the adrenergic lineage. We propose that elucidation of Signalling Regulatory Networks can augment and complement GRNs in characterising cell identities, which will in turn contribute to the design of improved therapeutics tailored to primary and relapsing neuroblastoma.

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Section: Is Wnt Signalling a Major Determinant Of Nc And Nb Cell Fate?mentioning

confidence: 82%

Section: Differentiation Of the Neural Crest And Wnt Signallingmentioning

confidence: 99%

Wnt signalling is a major determinant of neuroblastoma cell lineages

Szemes

Greenhough

Malik

2018

Preprint

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“…Moreover, a large number of studies have demonstrated that the MYCN gene is closely related to neuroblastoma . A study by Zaatiti et al indicated that neuroblastoma IMR‐32 cell lines had significantly decreased proliferation ability after MYCN knockout .…”

Section: Discussionmentioning

confidence: 99%

MYCN gene polymorphisms and Wilms tumor susceptibility in Chinese children

Huang

Zhao

Zhu

et al. 2019

Clinical Laboratory Analysis

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Background Wilms tumor, derived from embryonic cells, accounts for a large proportion of pediatric renal tumors. MYCN encoded by MYCN proto‐oncogene, a member of the MYC family, is a BHLH transcription factor. It plays a critical role in tumorigenesis and predicts poor clinical outcomes in various types of cancer. However, the role of MYCN remained unclarified in Wilms tumor. In this study, we investigated the association between MYCN gene polymorphisms and Wilms tumor susceptibility. Methods Four MYCN gene polymorphisms (rs57961569 G > A, rs9653226 T > C, rs13034994 A > G, and rs60226897 G > A) were genotyped in 183 cases and 603 controls. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated to evaluate the association between MYCN gene polymorphisms and Wilms tumor susceptibility. Results Overall, no significant association was found for any of the four MYCN gene polymorphisms. Interestingly, in the stratification analysis, the rs57961569 was found to be associated with decreased Wilms tumor susceptibility in the children older than 18 months (AOR = 0.65, 95% CI = 0.42‐1.00, P = .050). Moreover, older children carrying 2‐4 risk genotypes were at increased risk of Wilms tumor (OR = 1.55, 95% CI = 1.001‐2.40, P = .0497). Haplotype GCAA was shown to significantly increased Wilms tumor risk (AOR = 2.40, 95% CI = 1.12‐5.14, P = .024). Conclusion Our study demonstrated that these MYCN gene polymorphisms might be low penetrant variants in Wilms tumor.

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“…Although both MYCN and MYC upregulation occurs in the childhood cancer neuroblastoma, elevated MYCN is the strongest predictor of a poor prognosis [ 54 ]. Given that MYC, not MYCN, is normally expressed in neural crest cells early in chick development, MYCN amplification likely drives aberrant cell specification towards a CNS-like fate to increase tumour aggressiveness, while increased MYC in cells developmentally programmed to express MYC could explain a reduced pathogenicity [ 55 ].…”

Section: Neural Development In Nonmammalian Vertebrates Is Controlmentioning

confidence: 99%

MYC in Brain Development and Cancer

Zaytseva

Kim

Quinn

2020

IJMS

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The MYC family of transcriptional regulators play significant roles in animal development, including the renewal and maintenance of stem cells. Not surprisingly, given MYC’s capacity to promote programs of proliferative cell growth, MYC is frequently upregulated in cancer. Although members of the MYC family are upregulated in nervous system tumours, the mechanisms of how elevated MYC promotes stem cell-driven brain cancers is unknown. If we are to determine how increased MYC might contribute to brain cancer progression, we will require a more complete understanding of MYC’s roles during normal brain development. Here, we evaluate evidence for MYC family functions in neural stem cell fate and brain development, with a view to better understand mechanisms of MYC-driven neural malignancies.

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Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma

Cited by 40 publications

References 70 publications

Wnt signalling is a major determinant of neuroblastoma cell lineages

Wnt signalling is a major determinant of neuroblastoma cell lineages

MYCN gene polymorphisms and Wilms tumor susceptibility in Chinese children

MYC in Brain Development and Cancer

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