Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62629-6 |
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| author | Willemijn Breunis Eva Brack Anna C. Ehlers Ingrid Bechtold Samanta Kisele Jakob Wurth Lieke Mous Dorita Zabele Fabio Steffen Felina Zahnow Christian Britschgi Lorenz Bankel Christian Rothermundt Cornelia Vetter Daniel Müller Sander Botter Chantal Pauli Peter Bode Beate Rinner Jean-Pierre Bourquin Jochen Roessler Thomas G. P. Grünewald Beat W. Schäfer Didier Surdez Marco Wachtel |
| author_facet | Willemijn Breunis Eva Brack Anna C. Ehlers Ingrid Bechtold Samanta Kisele Jakob Wurth Lieke Mous Dorita Zabele Fabio Steffen Felina Zahnow Christian Britschgi Lorenz Bankel Christian Rothermundt Cornelia Vetter Daniel Müller Sander Botter Chantal Pauli Peter Bode Beate Rinner Jean-Pierre Bourquin Jochen Roessler Thomas G. P. Grünewald Beat W. Schäfer Didier Surdez Marco Wachtel |
| author_sort | Willemijn Breunis |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-58a985bea3b34d7f82eb0988bd351608 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-58a985bea3b34d7f82eb0988bd3516082025-08-24T11:38:18ZengNature PortfolioNature Communications2041-17232025-08-0116111610.1038/s41467-025-62629-6Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic targetWillemijn Breunis0Eva Brack1Anna C. Ehlers2Ingrid Bechtold3Samanta Kisele4Jakob Wurth5Lieke Mous6Dorita Zabele7Fabio Steffen8Felina Zahnow9Christian Britschgi10Lorenz Bankel11Christian Rothermundt12Cornelia Vetter13Daniel Müller14Sander Botter15Chantal Pauli16Peter Bode17Beate Rinner18Jean-Pierre Bourquin19Jochen Roessler20Thomas G. P. Grünewald21Beat W. Schäfer22Didier Surdez23Marco Wachtel24Department of Oncology and Children’s Research Center, University Children’s Hospital, University of ZurichDivision of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University HospitalHopp-Children’s Cancer Center (KiTZ)Department of Oncology and Children’s Research Center, University Children’s Hospital, University of ZurichDepartment of Oncology and Children’s Research Center, University Children’s Hospital, University of ZurichDepartment of Oncology and Children’s Research Center, University Children’s Hospital, University of ZurichBalgrist University Hospital, Faculty of Medicine, University of Zurich (UZH)Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH)Department of Oncology and Children’s Research Center, University Children’s Hospital, University of ZurichHopp-Children’s Cancer Center (KiTZ)Department of Medical Oncology and Hematology, University Hospital Zurich, Comprehensive Cancer Center ZurichDepartment of Medical Oncology and Hematology, University Hospital Zurich, Comprehensive Cancer Center ZurichDepartment of Medical Oncology and Hematology, Cantonal Hospital St. GallenDivision of Pediatric Hematology/Oncology, Children’s Hospital of Eastern SwitzerlandUniversity Sarcoma Center Zürich (CCCZ), Balgrist University Hospital, University of ZurichSwiss Center for Musculoskeletal Biobanking, Balgrist Campus AGDepartment of Pathology and Molecular Pathology, University Hospital ZurichDepartment of Pathology and Molecular Pathology, University Hospital ZurichDivision of Biomedical Research, Medical University of GrazDepartment of Oncology and Children’s Research Center, University Children’s Hospital, University of ZurichDivision of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University HospitalHopp-Children’s Cancer Center (KiTZ)Department of Oncology and Children’s Research Center, University Children’s Hospital, University of ZurichBalgrist University Hospital, Faculty of Medicine, University of Zurich (UZH)Department of Oncology and Children’s Research Center, University Children’s Hospital, University of ZurichAbstract 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.https://doi.org/10.1038/s41467-025-62629-6 |
| spellingShingle | Willemijn Breunis Eva Brack Anna C. Ehlers Ingrid Bechtold Samanta Kisele Jakob Wurth Lieke Mous Dorita Zabele Fabio Steffen Felina Zahnow Christian Britschgi Lorenz Bankel Christian Rothermundt Cornelia Vetter Daniel Müller Sander Botter Chantal Pauli Peter Bode Beate Rinner Jean-Pierre Bourquin Jochen Roessler Thomas G. P. Grünewald Beat W. Schäfer Didier Surdez Marco Wachtel Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target Nature Communications |
| title | Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target |
| title_full | Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target |
| title_fullStr | Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target |
| title_full_unstemmed | Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target |
| title_short | Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target |
| title_sort | patient derived tumoroids from cic dux4 rearranged sarcoma identify mcl1 as a therapeutic target |
| url | https://doi.org/10.1038/s41467-025-62629-6 |
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