2. Academic Validation
  3. Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

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

  • Nat Commun. 2021 Mar 3;12(1):1407. doi: 10.1038/s41467-021-21675-6.
Lars Custers  # 1 2,  Eleonora Khabirova  # 3,  Tim H H Coorens  # 3,  Thomas R W Oliver 3 4 5,  Camilla Calandrini 1 2,  Matthew D Young 3,  Felipe A Vieira Braga 6,  Peter Ellis 3,  Lira Mamanova 3,  Heidi Segers 7,  Arie Maat 1,  Marcel Kool 1 8 9,  Eelco W Hoving 1,  Marry M van den Heuvel-Eibrink 1,  James Nicholson 4 10,  Karin Straathof 11 12,  Liz Hook 4 5,  Ronald R de Krijger 1 13,  Claire Trayers 4,  Kieren Allinson 4,  Sam Behjati 14 15 16,  Jarno Drost 17 18
Affiliations

Affiliations

  • 1 Princess Máxima Center for Pediatric Oncology, 3584CS, Utrecht, the Netherlands.
  • 2 Oncode Institute, 3584CS, Utrecht, the Netherlands.
  • 3 Wellcome Sanger Institute, Hinxton, Saffron Walden, CB10 1SA, UK.
  • 4 Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.
  • 5 Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
  • 6 Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
  • 7 Department of Pediatric Hemato-Oncology, University Hospital Leuven, Leuven, Belgium.
  • 8 Hopp Children's Cancer Center (KiTZ), 69120, Heidelberg, Germany.
  • 9 Division of Pediatric Neurooncology, German Cancer Research Center DKFZ and German Cancer Consortium DKTK, 69120, Heidelberg, Germany.
  • 10 Department of Paediatrics, University of Cambridge, Cambridge, CB2 0QQ, UK.
  • 11 UCL Great Ormond Street Hospital Institute of Child Health Biomedical Research Centre, London, WC1N 1EH, UK.
  • 12 Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
  • 13 Department of Pathology, University Medical Center Utrecht, 3584CX, Utrecht, the Netherlands.
  • 14 Wellcome Sanger Institute, Hinxton, Saffron Walden, CB10 1SA, UK. sb31@sanger.ac.uk.
  • 15 Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK. sb31@sanger.ac.uk.
  • 16 Department of Paediatrics, University of Cambridge, Cambridge, CB2 0QQ, UK. sb31@sanger.ac.uk.
  • 17 Princess Máxima Center for Pediatric Oncology, 3584CS, Utrecht, the Netherlands. J.Drost@prinsesmaximacentrum.nl.
  • 18 Oncode Institute, 3584CS, Utrecht, the Netherlands. J.Drost@prinsesmaximacentrum.nl.
  • # Contributed equally.
PMID: 33658498 DOI: 10.1038/s41467-021-21675-6
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.

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