Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma
The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT's regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as susceptibility to pharmacologic inhibition and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.
Authors
- Jonas V. Schaefer (ORCID: https://orcid.org/0000-0002-8332-4371)
- Stefan Fröhling (ORCID: https://orcid.org/0000-0001-7907-4595)
- Birgit Dreier (ORCID: https://orcid.org/0000-0002-5124-9346)
- Kwang Seok Lee (ORCID: https://orcid.org/0000-0001-7682-5736)
- Martin Schneider (ORCID: https://orcid.org/0000-0001-5907-3587)
- Marie Groth
- Florian Iser (ORCID: https://orcid.org/0009-0003-6514-817X)
- Dominic Helm (ORCID: https://orcid.org/0000-0001-9321-2069)
- Cihan Erkut (ORCID: https://orcid.org/0000-0003-4378-9075)
- Claudia Scholl (ORCID: https://orcid.org/0000-0001-6768-322X)
- Philipp Walch (ORCID: https://orcid.org/0000-0002-7978-5685)
- Simon Linder (ORCID: https://orcid.org/0000-0002-3315-305X)
- Joana Marinho (ORCID: https://orcid.org/0000-0001-9001-9378)
- Kevin Mellert (ORCID: https://orcid.org/0000-0001-6338-1857)
- Jonas N. Kapp (ORCID: https://orcid.org/0000-0002-7308-559X)
- Simay Dolaner (ORCID: https://orcid.org/0000-0003-2411-8559)
- Andreas Plückthun (ORCID: https://orcid.org/0000-0003-4191-5306)
- Thomas F.E. Barth (ORCID: https://orcid.org/0000-0002-3379-6311)
- Charles S. Umbaugh (ORCID: https://orcid.org/0000-0002-9241-2971)
- Asli Kayserili
- Julia Hartmann
- Petra Schroeter
Institutions
- German Cancer Research Center (DE)
- Universität Ulm (DE)
- University of Zurich (CH)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- National Center for Tumor Diseases (DE)
- European Molecular Biology Laboratory (DE)
- DKFZ-ZMBH Alliance (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-09-03
- DOI
- https://doi.org/10.1126/sciadv.adu2796
- Citations
- 3
- Primary Topic
- Bone Tumor Diagnosis and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 5.00