A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations.
Nat Commun
; 15(1): 3745, 2024 May 03.
Article
em En
| MEDLINE
| ID: mdl-38702304
ABSTRACT
Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNAs impair the specification of trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. This effect is exacerbated upon overexpression of MYCN, whose amplification co-occurs with CNAs in NB. Moreover, CNAs potentiate the pro-tumourigenic effects of MYCN and mutant NC cells resemble NB cells in tumours. These changes correlate with a stepwise aberration of developmental transcription factor networks. Together, our results sketch a mechanistic framework for the CNA-driven initiation of embryonal tumours.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Diferenciação Celular
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Variações do Número de Cópias de DNA
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Proteína Proto-Oncogênica N-Myc
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Crista Neural
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Neuroblastoma
Limite:
Female
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article