Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma
Open accessPublished version of a preprint
Abstract
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.
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- Authors
- Umbaugh, C. S., Groth, M., Erkut, C., Lee, K.-S., Marinho, J., Linder, S., Iser, F., Kapp, J. N., Schroeter, P., Dolaner, S., Kayserili, A., Helm, D., Schneider, M., Hartmann, J., Walch, P., Barth, T. F. E., Mellert, K., Dreier, B., Schaefer, J. V., Plückthun, A., Fröhling, S., & Scholl, C.
- Affiliations
- German Cancer Research Center (DE)
- University of Zurich (CH)
- Universität Ulm (DE)
- Corresponding author
- Umbaugh, Charles S.
- Groth, Marie
- Fröhling, Stefan
- Scholl, Claudia
- ORCID
- Venue
- Science Advances
- Published
- 2025-09-05
- Volume
- 11
- Issue
- 36
- Pages
- eadu2796-eadu2796
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC12407079
- OpenAlex
- W4413973014
- Cited by
- 6
- References
- 7
- Citations by year
- 2026: 4 · 2025: 2
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Science Advances (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- chordoma, Brachyury, DARPin, interferon signaling, JAK2 inhibitors, IGFBP-3, cell cycle regulation, senescence, tumor differentiation, transcriptional regulatory networks, therapeutic vulnerabilities
- MeSH terms
- Animals, Chordoma, Humans, Gene Expression Regulation, Neoplastic, Xenograft Model Antitumor Assays, Proteomics, Cell Line, Tumor, Mice, Gene Regulatory Networks
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