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 van den Heuvel-Eibrink, James Nicholson, Karin Straathof, Liz Hook, Ronald R de Krijger, Claire Trayers, Kieren AllinsonSam Behjati, Jarno Drost

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

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.

Original languageEnglish
Article number1407
Pages (from-to)1407
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - 3 Mar 2021

Keywords

  • Cell Differentiation/genetics
  • DNA Methylation
  • Drug Screening Assays, Antitumor
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic/drug effects
  • Histone Deacetylase Inhibitors/pharmacology
  • Humans
  • Mutation
  • Neural Crest/pathology
  • Phylogeny
  • Rhabdoid Tumor/drug therapy
  • SMARCB1 Protein/genetics
  • Single-Cell Analysis
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • Tissue Culture Techniques/methods

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