Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition
Abstract Small round cell sarcomas (SRCS) are highly aggressive tumors in soft tissues and bone of mostly children and young adults. Despite being different in many aspects, including genetics, possible cell-of-origin, and pathology, patients with any of these entities all receive the same therapeut...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62673-2 |
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| author | Femke C. A. S. Ringnalda Gijs J. F. van Son Laurens H. G. Verweij Seok-Young Kim Vicky Amo-Addae Uta E. Flucke Laura S. Hiemcke–Jiwa Karin P. S. Langenberg Jos A. M. Bramer Lotte Heimans Michiel A. J. van de Sande Winan J. van Houdt Max M. van Noesel Hinri H. D. Kerstens Marcel Santoso Georg Seifert Olivier Delattre Katia Scotlandi Birgit Geoerger Johannes H. M. Merks Jan J. Molenaar Ruben van Boxtel Marc van de Wetering Karin Sanders Hans Clevers |
| author_facet | Femke C. A. S. Ringnalda Gijs J. F. van Son Laurens H. G. Verweij Seok-Young Kim Vicky Amo-Addae Uta E. Flucke Laura S. Hiemcke–Jiwa Karin P. S. Langenberg Jos A. M. Bramer Lotte Heimans Michiel A. J. van de Sande Winan J. van Houdt Max M. van Noesel Hinri H. D. Kerstens Marcel Santoso Georg Seifert Olivier Delattre Katia Scotlandi Birgit Geoerger Johannes H. M. Merks Jan J. Molenaar Ruben van Boxtel Marc van de Wetering Karin Sanders Hans Clevers |
| author_sort | Femke C. A. S. Ringnalda |
| collection | DOAJ |
| description | Abstract Small round cell sarcomas (SRCS) are highly aggressive tumors in soft tissues and bone of mostly children and young adults. Despite being different in many aspects, including genetics, possible cell-of-origin, and pathology, patients with any of these entities all receive the same therapeutic regimen. Although several pre-clinical models of Ewing sarcoma have been established, such as cell lines and patient-derived tumor xenografts, few models exist for other SRCS. Here, we describe a pediatric SRCS tumor organoid (tumoroid) biobank containing long-term tumoroid cultures with different translocations, including EWSR1::FLI1, EWSR1::ERG, CIC::DUX4, and BCOR-rearrangements. Using histology, whole genome sequencing and RNA sequencing, we demonstrate that these tumoroids retain histological characteristics, known marker gene expression and chromosomal rearangements of their matching patient tumors. In addition, we compare mutation clusters in the tumoroids across patient-matched longitudinal samples, which shows that cellular heterogeneity is maintained. Drug screening on the tumoroid models unveils entity-specific drug sensitivity to various cytotoxic compounds and targeted compounds, including MCL-1 inhibitors for CIC::DUX4 sarcomas. Taken together, this newly established SRCS patient-derived tumoroid biobank represents a promising source of material for future basic cancer research and drug screening. |
| format | Article |
| id | doaj-art-e41cda9b9a1141cfa59fa4f4690c29e4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e41cda9b9a1141cfa59fa4f4690c29e42025-08-24T11:39:08ZengNature PortfolioNature Communications2041-17232025-08-0116111610.1038/s41467-025-62673-2Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibitionFemke C. A. S. Ringnalda0Gijs J. F. van Son1Laurens H. G. Verweij2Seok-Young Kim3Vicky Amo-Addae4Uta E. Flucke5Laura S. Hiemcke–Jiwa6Karin P. S. Langenberg7Jos A. M. Bramer8Lotte Heimans9Michiel A. J. van de Sande10Winan J. van Houdt11Max M. van Noesel12Hinri H. D. Kerstens13Marcel Santoso14Georg Seifert15Olivier Delattre16Katia Scotlandi17Birgit Geoerger18Johannes H. M. Merks19Jan J. Molenaar20Ruben van Boxtel21Marc van de Wetering22Karin Sanders23Hans Clevers24Princess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologySarcomas and GIST Center, Netherlands Cancer Institute—Antoni van Leeuwenhoek (NKI-AVL)Princess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyDepartment of Pediatrics, Division of Oncology and Hematology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu BerlinInstitut Curie Research Center, NSERM U1330, Diversity and Plasticity of Pediatric Sarcoma Lab, PSL Research University, SIREDO Oncology CenterLaboratory of Experimental Oncology, IRCCS Istituto Ortopedico RizzoliDepartment of Pediatric and Adolescent Oncology, INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-SaclayPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyPrincess Máxima Center for Pediatric OncologyAbstract Small round cell sarcomas (SRCS) are highly aggressive tumors in soft tissues and bone of mostly children and young adults. Despite being different in many aspects, including genetics, possible cell-of-origin, and pathology, patients with any of these entities all receive the same therapeutic regimen. Although several pre-clinical models of Ewing sarcoma have been established, such as cell lines and patient-derived tumor xenografts, few models exist for other SRCS. Here, we describe a pediatric SRCS tumor organoid (tumoroid) biobank containing long-term tumoroid cultures with different translocations, including EWSR1::FLI1, EWSR1::ERG, CIC::DUX4, and BCOR-rearrangements. Using histology, whole genome sequencing and RNA sequencing, we demonstrate that these tumoroids retain histological characteristics, known marker gene expression and chromosomal rearangements of their matching patient tumors. In addition, we compare mutation clusters in the tumoroids across patient-matched longitudinal samples, which shows that cellular heterogeneity is maintained. Drug screening on the tumoroid models unveils entity-specific drug sensitivity to various cytotoxic compounds and targeted compounds, including MCL-1 inhibitors for CIC::DUX4 sarcomas. Taken together, this newly established SRCS patient-derived tumoroid biobank represents a promising source of material for future basic cancer research and drug screening.https://doi.org/10.1038/s41467-025-62673-2 |
| spellingShingle | Femke C. A. S. Ringnalda Gijs J. F. van Son Laurens H. G. Verweij Seok-Young Kim Vicky Amo-Addae Uta E. Flucke Laura S. Hiemcke–Jiwa Karin P. S. Langenberg Jos A. M. Bramer Lotte Heimans Michiel A. J. van de Sande Winan J. van Houdt Max M. van Noesel Hinri H. D. Kerstens Marcel Santoso Georg Seifert Olivier Delattre Katia Scotlandi Birgit Geoerger Johannes H. M. Merks Jan J. Molenaar Ruben van Boxtel Marc van de Wetering Karin Sanders Hans Clevers Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition Nature Communications |
| title | Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition |
| title_full | Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition |
| title_fullStr | Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition |
| title_full_unstemmed | Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition |
| title_short | Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition |
| title_sort | small round cell sarcoma tumoroid biobank reveals cic dux4 sarcoma vulnerability to mcl 1 inhibition |
| url | https://doi.org/10.1038/s41467-025-62673-2 |
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