Home > Publications database > Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma. > print

001     304303
005     20251024115534.0
024 7 _ |a 10.1126/sciadv.adu2796
|2 doi
024 7 _ |a pmid:40901948
|2 pmid
024 7 _ |a altmetric:181083185
|2 altmetric
037 _ _ |a DKFZ-2025-01838
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Umbaugh, Charles Samuel
|0 P:(DE-He78)2ada0592b32434a4f3a114f8541a49df
|b 0
|e First author
|u dkfz
245 _ _ |a Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma.
260 _ _ |a Washington, DC [u.a.]
|c 2025
|b Assoc.
336 7 _ |a article
|2 DRIVER
336 7 _ |a Output Types/Journal article
|2 DataCite
336 7 _ |a Journal Article
|b journal
|m journal
|0 PUB:(DE-HGF)16
|s 1756991051_27123
|2 PUB:(DE-HGF)
336 7 _ |a ARTICLE
|2 BibTeX
336 7 _ |a JOURNAL_ARTICLE
|2 ORCID
336 7 _ |a Journal Article
|0 0
|2 EndNote
500 _ _ |a #EA:B290#EA:B340#LA:B290#LA:B340#
520 _ _ |a 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.
536 _ _ |a 312 - Funktionelle und strukturelle Genomforschung (POF4-312)
|0 G:(DE-HGF)POF4-312
|c POF4-312
|f POF IV
|x 0
588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Gene Regulatory Networks
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Chordoma: metabolism
|2 MeSH
650 _ 2 |a Chordoma: genetics
|2 MeSH
650 _ 2 |a Chordoma: drug therapy
|2 MeSH
650 _ 2 |a Chordoma: pathology
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Gene Expression Regulation, Neoplastic: drug effects
|2 MeSH
650 _ 2 |a Proteomics
|2 MeSH
650 _ 2 |a Xenograft Model Antitumor Assays
|2 MeSH
700 1 _ |a Groth, Marie
|0 P:(DE-He78)15d736cdf8dab5782e1886ec4de9b66b
|b 1
|e First author
700 1 _ |a Erkut, Cihan
|0 P:(DE-He78)d7313b8a98b50ec1018453ef11351acc
|b 2
|u dkfz
700 1 _ |a Lee, Kwang
|0 P:(DE-He78)1121dc6777ecb3a3e48075bbd16246f2
|b 3
|u dkfz
700 1 _ |a Marinho, Joana
|0 0000-0001-9001-9378
|b 4
700 1 _ |a Linder, Simon
|0 P:(DE-He78)4e47fdea8ed35a69da75bc9a30971c49
|b 5
|u dkfz
700 1 _ |a Iser, Florian
|0 P:(DE-He78)3a5c3ccb1136028578b6bc8fe12b3019
|b 6
|u dkfz
700 1 _ |a Kapp, Jonas
|0 P:(DE-He78)d67102d44b98abd3243bcf44928048c4
|b 7
700 1 _ |a Schroeter, Petra
|0 P:(DE-He78)93543b4d8961fb093bcf0c86db648b2b
|b 8
|u dkfz
700 1 _ |a Dolaner, Simay
|0 P:(DE-He78)9128c030ab4aecc83482354694bae75f
|b 9
|u dkfz
700 1 _ |a Kayserili, Asli
|0 0009-0002-0737-0664
|b 10
700 1 _ |a Helm, Dominic
|0 P:(DE-He78)daaed5a5b968028e6e95d273150d5ab1
|b 11
|u dkfz
700 1 _ |a Schneider, Martin
|0 P:(DE-He78)0d37cc734b95fed555f2244d6fee6320
|b 12
|u dkfz
700 1 _ |a Hartmann, Julia
|0 P:(DE-He78)17112a5a72f44d4df00e64edc925d674
|b 13
700 1 _ |a Walch, Philipp
|0 P:(DE-He78)be5d291ecdf9748a9b74f3f4d37d1c5b
|b 14
700 1 _ |a Barth, Thomas F E
|b 15
700 1 _ |a Mellert, Kevin
|0 0000-0001-6338-1857
|b 16
700 1 _ |a Dreier, Birgit
|b 17
700 1 _ |a Schaefer, Jonas V
|0 0000-0002-8332-4371
|b 18
700 1 _ |a Plückthun, Andreas
|0 0000-0003-4191-5306
|b 19
700 1 _ |a Fröhling, Stefan
|0 P:(DE-He78)f0144d171d26dbedb67c9db1df35629d
|b 20
|e Last author
700 1 _ |a Scholl, Claudia
|0 P:(DE-He78)2c1a21d1cf5fdc9e297512c9d1354250
|b 21
|e Last author
|u dkfz
773 _ _ |a 10.1126/sciadv.adu2796
|g Vol. 11, no. 36, p. eadu2796
|0 PERI:(DE-600)2810933-8
|n 36
|p eadu2796
|t Science advances
|v 11
|y 2025
|x 2375-2548
909 C O |o oai:inrepo02.dkfz.de:304303
|p VDB
|p OpenAPC
|p openCost
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 0
|6 P:(DE-He78)2ada0592b32434a4f3a114f8541a49df
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 1
|6 P:(DE-He78)15d736cdf8dab5782e1886ec4de9b66b
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 2
|6 P:(DE-He78)d7313b8a98b50ec1018453ef11351acc
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 3
|6 P:(DE-He78)1121dc6777ecb3a3e48075bbd16246f2
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 5
|6 P:(DE-He78)4e47fdea8ed35a69da75bc9a30971c49
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 6
|6 P:(DE-He78)3a5c3ccb1136028578b6bc8fe12b3019
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 7
|6 P:(DE-He78)d67102d44b98abd3243bcf44928048c4
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 8
|6 P:(DE-He78)93543b4d8961fb093bcf0c86db648b2b
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 9
|6 P:(DE-He78)9128c030ab4aecc83482354694bae75f
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 10
|6 0009-0002-0737-0664
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 11
|6 P:(DE-He78)daaed5a5b968028e6e95d273150d5ab1
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 12
|6 P:(DE-He78)0d37cc734b95fed555f2244d6fee6320
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 13
|6 P:(DE-He78)17112a5a72f44d4df00e64edc925d674
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 14
|6 P:(DE-He78)be5d291ecdf9748a9b74f3f4d37d1c5b
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 20
|6 P:(DE-He78)f0144d171d26dbedb67c9db1df35629d
910 1 _ |a Deutsches Krebsforschungszentrum
|0 I:(DE-588b)2036810-0
|k DKFZ
|b 21
|6 P:(DE-He78)2c1a21d1cf5fdc9e297512c9d1354250
913 1 _ |a DE-HGF
|b Gesundheit
|l Krebsforschung
|1 G:(DE-HGF)POF4-310
|0 G:(DE-HGF)POF4-312
|3 G:(DE-HGF)POF4
|2 G:(DE-HGF)POF4-300
|4 G:(DE-HGF)POF
|v Funktionelle und strukturelle Genomforschung
|x 0
914 1 _ |y 2025
915 _ _ |a JCR
|0 StatID:(DE-HGF)0100
|2 StatID
|b SCI ADV : 2022
|d 2024-12-18
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0200
|2 StatID
|b SCOPUS
|d 2024-12-18
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0300
|2 StatID
|b Medline
|d 2024-12-18
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0501
|2 StatID
|b DOAJ Seal
|d 2024-05-14T07:33:42Z
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0500
|2 StatID
|b DOAJ
|d 2024-05-14T07:33:42Z
915 _ _ |a Peer Review
|0 StatID:(DE-HGF)0030
|2 StatID
|b DOAJ : Anonymous peer review
|d 2024-05-14T07:33:42Z
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0600
|2 StatID
|b Ebsco Academic Search
|d 2024-12-18
915 _ _ |a Peer Review
|0 StatID:(DE-HGF)0030
|2 StatID
|b ASC
|d 2024-12-18
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0199
|2 StatID
|b Clarivate Analytics Master Journal List
|d 2024-12-18
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1040
|2 StatID
|b Zoological Record
|d 2024-12-18
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)1150
|2 StatID
|b Current Contents - Physical, Chemical and Earth Sciences
|d 2024-12-18
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0160
|2 StatID
|b Essential Science Indicators
|d 2024-12-18
915 _ _ |a WoS
|0 StatID:(DE-HGF)0113
|2 StatID
|b Science Citation Index Expanded
|d 2024-12-18
915 _ _ |a DBCoverage
|0 StatID:(DE-HGF)0150
|2 StatID
|b Web of Science Core Collection
|d 2024-12-18
915 _ _ |a IF >= 10
|0 StatID:(DE-HGF)9910
|2 StatID
|b SCI ADV : 2022
|d 2024-12-18
915 _ _ |a Article Processing Charges
|0 StatID:(DE-HGF)0561
|2 StatID
|d 2024-12-18
915 _ _ |a Fees
|0 StatID:(DE-HGF)0700
|2 StatID
|d 2024-12-18
915 p c |a APC keys set
|2 APC
|0 PC:(DE-HGF)0000
915 p c |a Local Funding
|2 APC
|0 PC:(DE-HGF)0001
915 p c |a DFG OA Publikationskosten
|2 APC
|0 PC:(DE-HGF)0002
915 p c |a DOAJ Journal
|2 APC
|0 PC:(DE-HGF)0003
920 2 _ |0 I:(DE-He78)B290-20160331
|k B290
|l Angewandte Funktionelle Genomik
|x 0
920 2 _ |0 I:(DE-He78)B340-20160331
|k B340
|l Translationale Medizinische Onkologie
|x 1
920 1 _ |0 I:(DE-He78)B290-20160331
|k B290
|l Angewandte Funktionelle Genomik
|x 0
920 1 _ |0 I:(DE-He78)B340-20160331
|k B340
|l Translationale Medizinische Onkologie
|x 1
920 1 _ |0 I:(DE-He78)HD01-20160331
|k HD01
|l DKTK HD zentral
|x 2
920 1 _ |0 I:(DE-He78)W120-20160331
|k W120
|l Proteomics
|x 3
920 0 _ |0 I:(DE-He78)B290-20160331
|k B290
|l Angewandte Funktionelle Genomik
|x 0
920 0 _ |0 I:(DE-He78)B340-20160331
|k B340
|l Translationale Medizinische Onkologie
|x 1
980 _ _ |a journal
980 _ _ |a VDB
980 _ _ |a I:(DE-He78)B290-20160331
980 _ _ |a I:(DE-He78)B340-20160331
980 _ _ |a I:(DE-He78)HD01-20160331
980 _ _ |a I:(DE-He78)W120-20160331
980 _ _ |a UNRESTRICTED
980 _ _ |a APC

LibraryCollectionCLSMajorCLSMinorLanguageAuthor
Marc 21