A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations.
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ICR Authors
Authors
Saldana-Guerrero, IM
Montano-Gutierrez, LF
Boswell, K
Hafemeister, C
Poon, E
Shaw, LE
Stavish, D
Lea, RA
Wernig-Zorc, S
Bozsaky, E
Fetahu, IS
Zoescher, P
Pötschger, U
Bernkopf, M
Wenninger-Weinzierl, A
Sturtzel, C
Souilhol, C
Tarelli, S
Shoeb, MR
Bozatzi, P
Rados, M
Guarini, M
Buri, MC
Weninger, W
Putz, EM
Huang, M
Ladenstein, R
Andrews, PW
Barbaric, I
Cresswell, GD
Bryant, HE
Distel, M
Chesler, L
Taschner-Mandl, S
Farlik, M
Tsakiridis, A
Halbritter, F
Montano-Gutierrez, LF
Boswell, K
Hafemeister, C
Poon, E
Shaw, LE
Stavish, D
Lea, RA
Wernig-Zorc, S
Bozsaky, E
Fetahu, IS
Zoescher, P
Pötschger, U
Bernkopf, M
Wenninger-Weinzierl, A
Sturtzel, C
Souilhol, C
Tarelli, S
Shoeb, MR
Bozatzi, P
Rados, M
Guarini, M
Buri, MC
Weninger, W
Putz, EM
Huang, M
Ladenstein, R
Andrews, PW
Barbaric, I
Cresswell, GD
Bryant, HE
Distel, M
Chesler, L
Taschner-Mandl, S
Farlik, M
Tsakiridis, A
Halbritter, F
Document Type
Journal Article
Date
2024-05-03
Date Accepted
2024-04-15
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.
Citation
Nature Communications, 2024, 15 (1), pp. 3745 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Paediatric Tumour Biology