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@ARTICLE{Umbaugh:304303,
      author       = {C. S. Umbaugh$^*$ and M. Groth$^*$ and C. Erkut$^*$ and K.
                      Lee$^*$ and J. Marinho and S. Linder$^*$ and F. Iser$^*$ and
                      J. Kapp$^*$ and P. Schroeter$^*$ and S. Dolaner$^*$ and A.
                      Kayserili$^*$ and D. Helm$^*$ and M. Schneider$^*$ and J.
                      Hartmann$^*$ and P. Walch$^*$ and T. F. E. Barth and K.
                      Mellert and B. Dreier and J. V. Schaefer and A. Plückthun
                      and S. Fröhling$^*$ and C. Scholl$^*$},
      title        = {{S}elective targeting of {TBXT} with {DARP}ins identifies
                      regulatory networks and therapeutic vulnerabilities in
                      chordoma.},
      journal      = {Science advances},
      volume       = {11},
      number       = {36},
      issn         = {2375-2548},
      address      = {Washington, DC [u.a.]},
      publisher    = {Assoc.},
      reportid     = {DKFZ-2025-01838},
      pages        = {eadu2796},
      year         = {2025},
      note         = {#EA:B290#EA:B340#LA:B290#LA:B340#},
      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.},
      keywords     = {Humans / Animals / Gene Regulatory Networks / Mice /
                      Chordoma: metabolism / Chordoma: genetics / Chordoma: drug
                      therapy / Chordoma: pathology / Cell Line, Tumor / Gene
                      Expression Regulation, Neoplastic: drug effects / Proteomics
                      / Xenograft Model Antitumor Assays},
      cin          = {B290 / B340 / HD01 / W120},
      ddc          = {500},
      cid          = {I:(DE-He78)B290-20160331 / I:(DE-He78)B340-20160331 /
                      I:(DE-He78)HD01-20160331 / I:(DE-He78)W120-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40901948},
      doi          = {10.1126/sciadv.adu2796},
      url          = {https://inrepo02.dkfz.de/record/304303},
}