Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition

Femke C. A. S. Ringnalda, Gijs J. F. 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. Sande, Winan J. Houdt, Max M. Noesel, Hinri H. D. Kerstens, Marcel Santoso, Georg Seifert, Olivier Delattre, Katia Scotlandi, Birgit Geoerger, Johannes H. M. Merks, Jan J. Molenaar, Ruben Boxtel, Marc Wetering, Karin Sanders () and Hans Clevers ()
Additional contact information
Femke C. A. S. Ringnalda: Princess Máxima Center for Pediatric Oncology
Gijs J. F. Son: Princess Máxima Center for Pediatric Oncology
Laurens H. G. Verweij: Princess Máxima Center for Pediatric Oncology
Seok-Young Kim: Princess Máxima Center for Pediatric Oncology
Vicky Amo-Addae: Princess Máxima Center for Pediatric Oncology
Uta E. Flucke: Princess Máxima Center for Pediatric Oncology
Laura S. Hiemcke–Jiwa: Princess Máxima Center for Pediatric Oncology
Karin P. S. Langenberg: Princess Máxima Center for Pediatric Oncology
Jos A. M. Bramer: Princess Máxima Center for Pediatric Oncology
Lotte Heimans: Netherlands Cancer Institute—Antoni van Leeuwenhoek (NKI-AVL)
Michiel A. J. Sande: Princess Máxima Center for Pediatric Oncology
Winan J. Houdt: Princess Máxima Center for Pediatric Oncology
Max M. Noesel: Princess Máxima Center for Pediatric Oncology
Hinri H. D. Kerstens: Princess Máxima Center for Pediatric Oncology
Marcel Santoso: Princess Máxima Center for Pediatric Oncology
Georg Seifert: Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Olivier Delattre: NSERM U1330, Diversity and Plasticity of Pediatric Sarcoma Lab, PSL Research University, SIREDO Oncology Center
Katia Scotlandi: IRCCS Istituto Ortopedico Rizzoli
Birgit Geoerger: Université Paris-Saclay
Johannes H. M. Merks: Princess Máxima Center for Pediatric Oncology
Jan J. Molenaar: Princess Máxima Center for Pediatric Oncology
Ruben Boxtel: Princess Máxima Center for Pediatric Oncology
Marc Wetering: Princess Máxima Center for Pediatric Oncology
Karin Sanders: Princess Máxima Center for Pediatric Oncology
Hans Clevers: Princess Máxima Center for Pediatric Oncology

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62673-2

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