Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

Lars Custers, Eleonora Khabirova, Tim H. H. Coorens, Thomas R. W. Oliver, Camilla Calandrini, Matthew D. Young, Felipe A. Vieira Braga, Peter Ellis, Lira Mamanova, Heidi Segers, Arie Maat, Marcel Kool, Eelco W. Hoving, Marry M. Heuvel-Eibrink, James Nicholson, Karin Straathof, Liz Hook, Ronald R. Krijger, Claire Trayers, Kieren Allinson, Sam Behjati () and Jarno Drost ()
Additional contact information
Lars Custers: Princess Máxima Center for Pediatric Oncology
Eleonora Khabirova: Wellcome Sanger Institute
Tim H. H. Coorens: Wellcome Sanger Institute
Thomas R. W. Oliver: Wellcome Sanger Institute
Camilla Calandrini: Princess Máxima Center for Pediatric Oncology
Matthew D. Young: Wellcome Sanger Institute
Felipe A. Vieira Braga: University of Amsterdam
Peter Ellis: Wellcome Sanger Institute
Lira Mamanova: Wellcome Sanger Institute
Heidi Segers: University Hospital Leuven
Arie Maat: Princess Máxima Center for Pediatric Oncology
Marcel Kool: Princess Máxima Center for Pediatric Oncology
Eelco W. Hoving: Princess Máxima Center for Pediatric Oncology
Marry M. Heuvel-Eibrink: Princess Máxima Center for Pediatric Oncology
James Nicholson: Cambridge University Hospitals NHS Foundation Trust
Karin Straathof: UCL Great Ormond Street Hospital Institute of Child Health Biomedical Research Centre
Liz Hook: Cambridge University Hospitals NHS Foundation Trust
Ronald R. Krijger: Princess Máxima Center for Pediatric Oncology
Claire Trayers: Cambridge University Hospitals NHS Foundation Trust
Kieren Allinson: Cambridge University Hospitals NHS Foundation Trust
Sam Behjati: Wellcome Sanger Institute
Jarno Drost: Princess Máxima Center for Pediatric Oncology

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-21675-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21675-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-21675-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().