2. Academic Validation
  3. Small round cell sarcoma tumoroid biobank reveals CIC::DUX4 sarcoma vulnerability to MCL-1 inhibition

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

  • Nat Commun. 2025 Aug 21;16(1):7689. doi: 10.1038/s41467-025-62673-2.
Femke C A S Ringnalda 1 2,  Gijs J F van Son 1 2,  Laurens H G Verweij 1 2,  Seok-Young Kim 1 2,  Vicky Amo-Addae 1,  Uta E Flucke 1 3,  Laura S Hiemcke-Jiwa 1 4,  Karin P S Langenberg 1,  Jos A M Bramer 1,  Lotte Heimans 5,  Michiel A J van de Sande 1,  Winan J van Houdt 1 6,  Max M van Noesel 1,  Hinri H D Kerstens 1,  Marcel Santoso 1,  Georg Seifert 7,  Olivier Delattre 8,  Katia Scotlandi 9,  Birgit Geoerger 10,  Johannes H M Merks 1 11,  Jan J Molenaar 1,  Ruben van Boxtel 1 2,  Marc van de Wetering 1 2,  Karin Sanders # 12 13,  Hans Clevers # 14 15 16 17
Affiliations

Affiliations

  • 1 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • 2 Oncode Institute, Utrecht, The Netherlands.
  • 3 Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 4 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 5 Sarcomas and GIST Center, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, The Netherlands.
  • 6 Department of Surgical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, The Netherlands.
  • 7 Department of Pediatrics, Division of Oncology and Hematology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 8 Institut Curie Research Center, NSERM U1330, Diversity and Plasticity of Pediatric Sarcoma Lab, PSL Research University, SIREDO Oncology Center, Paris, France.
  • 9 Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
  • 10 Department of Pediatric and Adolescent Oncology, INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Paris, France.
  • 11 Division of Imaging and Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
  • 12 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. k.sanders@prinsesmaximacentrum.nl.
  • 13 Oncode Institute, Utrecht, The Netherlands. k.sanders@prinsesmaximacentrum.nl.
  • 14 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. h.clevers@hubrecht.eu.
  • 15 Oncode Institute, Utrecht, The Netherlands. h.clevers@hubrecht.eu.
  • 16 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, Utrecht, The Netherlands. h.clevers@hubrecht.eu.
  • 17 Pharma, Research and Early Development (pRED) of F. Hoffmann-La Roche Ltd, Basel, Switzerland. h.clevers@hubrecht.eu.
  • # Contributed equally.
PMID: 40841360 DOI: 10.1038/s41467-025-62673-2
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.

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