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

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 () and Marco Wachtel ()
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Willemijn Breunis: University of Zurich
Eva Brack: Bern University Hospital
Anna C. Ehlers: Hopp-Children’s Cancer Center (KiTZ)
Ingrid Bechtold: University of Zurich
Samanta Kisele: University of Zurich
Jakob Wurth: University of Zurich
Lieke Mous: University of Zurich (UZH)
Dorita Zabele: University of Zurich (UZH)
Fabio Steffen: University of Zurich
Felina Zahnow: Hopp-Children’s Cancer Center (KiTZ)
Christian Britschgi: Comprehensive Cancer Center Zurich
Lorenz Bankel: Comprehensive Cancer Center Zurich
Christian Rothermundt: Cantonal Hospital St. Gallen
Cornelia Vetter: Children’s Hospital of Eastern Switzerland
Daniel Müller: University of Zurich
Sander Botter: Balgrist Campus AG
Chantal Pauli: University Hospital Zurich
Peter Bode: University Hospital Zurich
Beate Rinner: Medical University of Graz
Jean-Pierre Bourquin: University of Zurich
Jochen Roessler: Bern University Hospital
Thomas G. P. Grünewald: Hopp-Children’s Cancer Center (KiTZ)
Beat W. Schäfer: University of Zurich
Didier Surdez: University of Zurich (UZH)
Marco Wachtel: University of Zurich

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

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62629-6

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