Journal Article

DKFZ-2023-00709

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities.

Paassen, I. ; Williams, J. ; Ríos Arceo, C. ; Ringnalda, F. ; Mercer, K. S. ; Buhl, J. L. ; Moreno, N. ; Federico, A.DKFZ* ; Franke, N. E. ; Kranendonk, M. ; Upadhyaya, S. A. ; Kerl, K. ; van de Wetering, M. ; Clevers, H. ; Kool, M.DKFZ* ; Hoving, E. W. ; Roussel, M. F. ; Drost, J.

2023
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41388-023-02681-y

Abstract: Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically defined by alterations in the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be further classified in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT-MYC and ATRT-SHH subgroups. Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to NOTCH inhibitors, which corresponded to high expression of NOTCH receptors. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing a representative pre-clinical model which enables the development of subgroup-specific therapies.

Note: 2023 May;42(20):1661-1671

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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