A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

SALDANA-GUERRERO, Ingrid M., MONTANO-GUTIERREZ, Luis F., BOSWELL, Katy, HAFEMEISTER, Christoph, POON, Evon, SHAW, Lisa E., STAVISH, Dylan, LEA, Rebecca A., WERNIG-ZORC, Sara, BOZSAKY, Eva, FETAHU, Irfete S., ZOESCHER, Peter, PÖTSCHGER, Ulrike, BERNKOPF, Marie, WENNINGER-WEINZIERL, Andrea, STURTZEL, Caterina, SOUILHOL, Celine, TARELLI, Sophia, SHOEB, Mohamed R., BOZATZI, Polyxeni, RADOS, Magdalena, GUARINI, Maria, BURI, Michelle C., WENINGER, Wolfgang, PUTZ, Eva M., HUANG, Miller, LADENSTEIN, Ruth, ANDREWS, Peter W., BARBARIC, Ivana, CRESSWELL, George D., BRYANT, Helen E., DISTEL, Martin, CHESLER, Louis, TASCHNER-MANDL, Sabine, FARLIK, Matthias, TSAKIRIDIS, Anestis and HALBRITTER, Florian (2024). A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations. Nature Communications, 15 (1).

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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.

Item Type:	Article
Additional Information:	** From Springer Nature via Jisc Publications Router ** Licence for this article: http://creativecommons.org/licenses/by/4.0/ ** Acknowledgements: We would like to thank the Biomedical Sequencing Facility at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences for assistance with next-generation sequencing, Bettina Brunner-Herglotz (CCRI) for her technical assistance, and Duncan Baker (Sheffield Diagnostic Genetic Services, Sheffield Children’s Hospital) for carrying out karyotyping of hESC lines. We would like to acknowledge Yann Jamin and Barbara Martins da Costa (ICR, London) for help with the MRI and animal work, respectively. We are also grateful to Igor Adameyko and Polina Kameneva (Medical University of Vienna), Sofie Mohlin (Lund University), and Christoph Bock (CeMM Research Center for Molecular Medicine) for critical reading of the manuscript. We would also like to thank Eszter Söjtöry (CCRI) and Jan Koster (Amsterdam UMC) for their help with providing interfaces for exploratory data analysis for our data. For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. The following funding sources contributed directly or indirectly to the support of this study: Alex’s Lemonade Stand Foundation for Childhood Cancer (ALSF) 20-17258 (M.D., M.F., F.H.); Austrian Academy of Sciences (OEAW) 25902 (M.C.B.); Austrian Research Promotion Agency (FFG) 7940628 533 (M.D.); Austrian Science Fund (FWF) 10.55776/P35072 (I.S.F.), 10.55776/P32001 (E.M.P.), 10.55776/P34832 (E.M.P.), 10.55776/P35841B (S.T.M.), 10.55776/TAI454 (F.H.), 10.55776/TAI732 (F.H.), 10.55776/PAT1300223 (F.H.); Biotechnology and Biological Sciences Research Council (BBSRC) BB/T007222/1 (K.B.), BB/P000444/1 (A.T.); Children’s Cancer and Leukaemia Group/Little Princess Trust CCLGA 2018 06 (H.E.B.), CCLGA 2020 19 (H.E.B., A.T.); Neuroblastoma UK/Children’s Cancer and Leukaemia Group/Little Princess Trust CCLGA 2019 28 (A.T.); CRUK Programme Award A28278 (E.P., L.C.); Donald E. and Delia B. Baxter Foundation Fellowship Award (M.H.); EC Horizon 2020 826494 (S.T.M.), 824070 (A.T.); Higher Education Funding Council for England (HEFCE) ICR (L.C.); Medical Research Council UK (MRC) MR/X000028/1 (I.B.), MR/X007979/1 (I.B.), MR/V002163/1 (A.T.); National Institutes of Health (NIH) R00CA197484 (M.H.); St. Anna Kinderkrebsforschung (E.M.P, R.L., G.C., M.D., S.T.M., F.H.); UK Regenerative Medicine Platform MR/R015724/1 (I.B.); Vienna Science and Technology Fund (WWTF) LS18-111 (S.T.M.). **Journal IDs: eissn 2041-1723 **Article IDs: publisher-id: s41467-024-47945-7; manuscript: 47945 **History: collection 01-12-2024; online 03-05-2024; published_online 03-05-2024; registration 17-04-2024; accepted 15-04-2024; submitted 06-01-2023
Identification Number:	https://doi.org/10.1038/s41467-024-47945-7
SWORD Depositor:	Colin Knott
Depositing User:	Colin Knott
Date Deposited:	10 May 2024 11:53
Last Modified:	10 May 2024 11:53
URI:	https://shura.shu.ac.uk/id/eprint/33675

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