2. Academic Validation
  3. Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target

Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target

  • Nat Commun. 2025 Aug 21;16(1):7688. doi: 10.1038/s41467-025-62629-6.
Willemijn Breunis # 1,  Eva Brack # 2,  Anna C Ehlers 3 4 5 6,  Ingrid Bechtold 1,  Samanta Kisele 1,  Jakob Wurth 1,  Lieke Mous 7,  Dorita Zabele 7,  Fabio Steffen 1,  Felina Zahnow 3,  Christian Britschgi 8 9,  Lorenz Bankel 8,  Christian Rothermundt 10,  Cornelia Vetter 11,  Daniel Müller 12,  Sander Botter 13,  Chantal Pauli 14,  Peter Bode 14,  Beate Rinner 15,  Jean-Pierre Bourquin 1,  Jochen Roessler 2,  Thomas G P Grünewald 3 4 5 16,  Beat W Schäfer 17,  Didier Surdez 18,  Marco Wachtel 19
Affiliations

Affiliations

  • 1 Department of Oncology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland.
  • 2 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, Bern, Switzerland.
  • 3 Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany.
  • 4 Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 5 National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
  • 6 Medical Faculty, Ruprecht-Karls-University, Heidelberg, Germany.
  • 7 Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland.
  • 8 Department of Medical Oncology and Hematology, University Hospital Zurich, Comprehensive Cancer Center Zurich, Zurich, Switzerland.
  • 9 Medical Oncology and Hematology, Cantonal Hospital Winterthur, Winterthur, Switzerland.
  • 10 Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
  • 11 Division of Pediatric Hematology/Oncology, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.
  • 12 University Sarcoma Center Zürich (CCCZ), Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
  • 13 Swiss Center for Musculoskeletal Biobanking, Balgrist Campus AG, Zurich, Switzerland.
  • 14 Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
  • 15 Division of Biomedical Research, Medical University of Graz, Graz, Austria.
  • 16 Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • 17 Department of Oncology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland. beat.schafer@kispi.uzh.ch.
  • 18 Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland. didier.surdez@balgrist.ch.
  • 19 Department of Oncology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland. marco.wachtel@kispi.uzh.ch.
  • # Contributed equally.
PMID: 40841513 DOI: 10.1038/s41467-025-62629-6
Abstract

High-risk sarcomas, such as metastatic and relapsed Ewing and CIC-rearranged sarcoma, still have a poor prognosis despite intensive therapeutic regimens. Precision medicine approaches offer hope, and ex vivo drug response profiling of patient-derived tumor cells emerges as a promising tool to identify effective therapies for individual patients. Here, we establish ex vivo culture conditions to propagate Ewing sarcoma and CIC::DUX4 sarcoma as tumoroids. These models retain their original molecular and functional characteristics, including recurrent ARID1A mutations in CIC::DUX4 sarcoma, and serve as tumor avatars for large-scale drug testing. Screening a large drug library on a small living biobank of such tumors not only reveals distinct differences in drug response between the two entities, but also identifies a dependency of CIC::DUX4 sarcoma cells on MCL1. Mechanistically, MCL1 is identified as a direct transcriptional target of the CIC::DUX4 fusion oncogene. Genetic and pharmacological inhibition of MCL1 induces rapid Apoptosis in CIC::DUX4 sarcoma cells and inhibits tumor growth in a xenograft model. Thus, MCL1 represents a potential therapeutic target for CIC::DUX4 sarcoma. Overall, our study highlights the feasibility of drug response profiling for individual sarcoma cases and suggests that further clinical assessments of its benefit are warranted.

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