| Literature DB >> 33658498 |
Lars Custers1,2, Eleonora Khabirova3, Tim H H Coorens3, Thomas R W Oliver3,4,5, Camilla Calandrini1,2, Matthew D Young3, Felipe A Vieira Braga6, Peter Ellis3, Lira Mamanova3, Heidi Segers7, Arie Maat1, Marcel Kool1,8,9, Eelco W Hoving1, Marry M van den Heuvel-Eibrink1, James Nicholson4,10, Karin Straathof11,12, Liz Hook4,5, Ronald R de Krijger1,13, Claire Trayers4, Kieren Allinson4, Sam Behjati14,15,16, Jarno Drost17,18.
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.Entities:
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Year: 2021 PMID： 33658498 DOI： 10.1038/s41467-021-21675-6
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919