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 Allinson; Sam Behjati; Jarno Drost

doi:10.1038/s41467-021-21675-6

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

3 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 language	English
Article number	1407
Pages (from-to)	1-11
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21675-6
Publication status	Published - 1 Dec 2021

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Custers, L., Khabirova, E., Coorens, T. H. H., Oliver, T. R. W., Calandrini, C., Young, M. D., Vieira Braga, F. A., Ellis, P., Mamanova, L., Segers, H., Maat, A., Kool, M., Hoving, E. W., van den Heuvel-Eibrink, M. M., Nicholson, J., Straathof, K., Hook, L., de Krijger, R. R., Trayers, C., ... Drost, J. (2021). Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours. Nature Communications, 12(1), 1-11. Article 1407. https://doi.org/10.1038/s41467-021-21675-6

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title = "Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours",

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.",

author = "Lars Custers and Eleonora Khabirova and Coorens, {Tim H.H.} and Oliver, {Thomas R.W.} and Camilla Calandrini and Young, {Matthew D.} and {Vieira Braga}, {Felipe A.} and Peter Ellis and Lira Mamanova and Heidi Segers and Arie Maat and Marcel Kool and Hoving, {Eelco W.} and {van den Heuvel-Eibrink}, {Marry M.} and James Nicholson and Karin Straathof and Liz Hook and {de Krijger}, {Ronald R.} and Claire Trayers and Kieren Allinson and Sam Behjati and Jarno Drost",

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Custers, L, Khabirova, E, Coorens, THH, Oliver, TRW, Calandrini, C, Young, MD, Vieira Braga, FA, Ellis, P, Mamanova, L, Segers, H, Maat, A, Kool, M, Hoving, EW, van den Heuvel-Eibrink, MM, Nicholson, J, Straathof, K, Hook, L, de Krijger, RR, Trayers, C, Allinson, K, Behjati, S & Drost, J 2021, 'Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours', Nature Communications, vol. 12, no. 1, 1407, pp. 1-11. https://doi.org/10.1038/s41467-021-21675-6

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T1 - Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

AU - Custers, Lars

AU - Khabirova, Eleonora

AU - Coorens, Tim H.H.

AU - Oliver, Thomas R.W.

AU - Calandrini, Camilla

AU - Young, Matthew D.

AU - Vieira Braga, Felipe A.

AU - Ellis, Peter

AU - Mamanova, Lira

AU - Segers, Heidi

AU - Maat, Arie

AU - Kool, Marcel

AU - Hoving, Eelco W.

AU - van den Heuvel-Eibrink, Marry M.

AU - Nicholson, James

AU - Straathof, Karin

AU - Hook, Liz

AU - de Krijger, Ronald R.

AU - Trayers, Claire

AU - Allinson, Kieren

AU - Behjati, Sam

AU - Drost, Jarno

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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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SP - 1

EP - 11

JO - Nature Communications

JF - Nature Communications

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M1 - 1407

ER -

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

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