PXD055982

PXD055982 is an original dataset announced via ProteomeXchange.

Title	Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma
Description	Aberrant expression of the embryonal transcription factor TBXT (also known as brachyury) drives chordoma, a rare spinal neoplasm with no effective drug therapies. The gene network regulated by TBXT is poorly understood, and strategies to disrupt its abnormal activity for therapeutic purposes are lacking. Here, we developed TBXT-targeted designed ankyrin repeat proteins (T-DARPins) that selectively bind TBXT, inhibiting its binding to DNA and expression. In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced morphologic changes indicative of senescence and differentiation. Combining T-DARPin-mediated TBXT inhibition with transcriptomic and proteomic analyses, we determined the TBXT regulome in chordoma cells, which comprises in particular networks involved in cell cycle regulation, DNA replication and repair, embryonal cell identity, metabolic processes, and interferon response. The analysis of selected TBXT regulome components provided new insights into chordoma biology, such as the strong upregulation of IGFBP3 upon TBXT inhibition to fine-tune part of TBXT’s downstream effectors. Finally, we assigned each TBXT regulome member a druggability status to create a resource for future translational studies and found high interferon response signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with strong sensitivity to clinically approved JAK2 inhibitors. These findings demonstrate the potential of DARPins to investigate the function of nuclear proteins to understand the regulatory networks of cancers driven by aberrant transcription factor activity, including novel entry points for targeted therapies that warrant testing in patients.
HostingRepository	PRIDE
AnnounceDate	2025-07-31
AnnouncementXML	Submission_2025-07-31_03:25:17.081.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Claudia Scholl
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480; Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-18 07:57:04	ID requested
⏵ 1	2025-07-31 03:25:17	announced

Dataset with its publication pending

submitter keyword: TBXT,Chordoma, DARPin, Brachyury

Claudia Scholl
contact affiliation	Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
contact email	claudia.scholl@nct-heidelberg.de
lab head
Claudia Scholl
contact affiliation	German Cancer Research Center (DKFZ)
contact email	claudia.scholl@nct-heidelberg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055982
     1. Label: PRIDE project
     2. Name: Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma