Die Bedeutung des Transkriptionsfaktors Brachyury in Chordomen

Zusammenfassung

Chordome sind seltene, maligne Knochentumoren, die vermutlich embryonalen Überresten der Chorda dorsalis entstammen. Ein wesentliches Argument für diese Annahme ist die gemeinsame Expression des Transkriptionsfaktors Brachyury.

Während Brachyury im Rahmen der Embryonalentwicklung für die Ausbildung der anterior-posterioren Achse von fundamentaler Bedeutung ist, legen neueste Studien nahe, dass Brachyury auch für das Überleben von Chordomen essenziell ist.

Dieser Beitrag liefert eine Übersicht über die physiologischen und onkogenen Funktionen von Brachyury und diskutiert die sich hieraus ableitenden therapeutischen Ansatzpunkte in Chordomen.

Abstract

Chordomas are rare, malignant bone tumors, which are thought to arise from notochordal remnants. This assumption is based on the shared expression of the transcription factor brachyury.

During embryonic development brachyury plays a crucial role during the formation of the anterior-posterior axis, however, recent studies provide convincing evidence, that brachyury is also essential for survival of chordoma cells.

This article provides an overview of the physiological and oncogenic functions of brachyury and discusses targeted therapeutic approaches in chordoma.

Publikationsverlauf

Artikel online veröffentlicht:
28. Februar 2023

• Literatur

• 1 Seeling C, Lechel A, Svinarenko M. et al. Molecular features and vulnerabilities of recurrent chordomas. J Exp Clin Cancer Res 2021; 40: 244 DOI: 10.1186/s13046-021-02037-y.
• 2 Flanagan AM, Yamaguchi T.. WHO Classification of Tumors and Soft Tissue and Bones. In: Fletcher CDM, Bridge JA, Hogendoorn PCW et al., Hrsg. WHO Classification of Tumors and Soft Tissue and Bones. 4. Aufl. Lyon: IARC Press; 2013: 328-329
• 3 Jäger D, Barth TFE, Brüderlein S. et al. HOXA7, HOXA9, and HOXA10 are differentially expressed in clival and sacral chordomas. Sci Rep 2017; 7: 2032 DOI: 10.1038/s41598-017-02174-5.
• 4 Holley C, Breining T, Scheithauer M. et al. Primäres extraaxiales chondroides Chordom des anterioren Nasenseptums: Fallbericht eines seltenen Chordoms mit Literaturübersicht. HNO 2021; 69: 221-228 DOI: 10.1007/s00106-020-00957-3.
• 5 Neumann J, Gersing AS, Barth TF. et al. Intra-articular extra-axial chordoma of the wrist: a case report with review of the current literature. Skeletal Radiol 2019; 48: 2015-2020 DOI: 10.1007/s00256-019-03228-7.
• 6 Yu J, Wang L, Jiang N. et al. A Rare Chordoma-The Epiglottic chordoma. Ear Nose Throat J 2022; DOI: 10.1177/01455613221132386. 10.1177/01455613221132386
• 7 Tarpey PS, Behjati S, Young MD. et al. The driver landscape of sporadic chordoma. Nat Commun 2017; 8: 890 DOI: 10.1038/s41467-017-01026-0.
• 8 Scheil S, Bruderlein S, Liehr T. et al. Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1. Genes Chromosomes Cancer 2001; 32: 203-211 DOI: 10.1002/gcc.1184.
• 9 von Witzleben A, Goerttler LT, Marienfeld R. et al. Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway. Cancer Res 2015; 75: 3823-3831 DOI: 10.1158/0008-5472.CAN-14-3270.
• 10 Presneau N, Shalaby A, Idowu B. et al. Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway. Br J Cancer 2009; 100: 1406-1414 DOI: 10.1038/sj.bjc.6605019.
• 11 Ptaszynski K, Szumera-Cieckiewicz A, Owczarek J. et al. Epidermal growth factor receptor (EGFR) status in chordoma. Pol J Pathol 2009; 60: 81-87
• 12 Brandal P, Bjerkehagen B, Danielsen H. et al. Chromosome 7 abnormalities are common in chordomas. Cancer Genet Cytogenet 2005; 160: 15-21 DOI: 10.1016/j.cancergencyto.2004.11.016.
• 13 Cates JM, Itani DM, Coffin CM. et al. The sonic hedgehog pathway in chordoid tumours. Histopathology 2010; 56: 978-979 DOI: 10.1111/j.1365-2559.2010.03572.x.
• 14 Yang XR, Ng D, Alcorta DA. et al. T (brachyury) gene duplication confers major susceptibility to familial chordoma. Nat Genet 2009; 41: 1176-1178 DOI: 10.1038/ng.454.
• 15 Kelley MJ, Shi J, Ballew B. et al. Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma. Hum Genet 2014; 133: 1289-1297 DOI: 10.1007/s00439-014-1463-z.
• 16 Pillay N, Plagnol V, Tarpey PS. et al. A common single-nucleotide variant in T is strongly associated with chordoma. Nat Genet 2012; 44: 1185-1187 DOI: 10.1038/ng.2419.
• 17 Kispert A, Herrmann BG.. The Brachyury gene encodes a novel DNA binding protein. EMBO J 1993; 12: 3211-3220 DOI: 10.1002/j.1460-2075.1993.tb05990.x.
• 18 Lolas M, Valenzuela PD, Tjian R. et al. Charting Brachyury-mediated developmental pathways during early mouse embryogenesis. Proc Natl Acad Sci U S A 2014; 111: 4478-4483 DOI: 10.1073/pnas.1402612111.
• 19 Vujovic S, Henderson S, Presneau N. et al. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol 2006; 209: 157-165 DOI: 10.1002/path.1969.
• 20 Dobrovolskaïa-Zavadskaïa N.. Sur la mortification spontanée de la queue chez la souris nouveaunée et sur l’existence d’un caractère heriditaire “non-viable”. C R. Soc Biol 1927; 97: 114-116
• 21 Gluecksohn-Schoenheimer S.. The Development of Two Tailless Mutants in the House Mouse. Genetics 1938; 23: 573-584 DOI: 10.1093/genetics/23.6.573.
• 22 Showell C, Binder O, Conlon FL.. T-box genes in early embryogenesis. Dev Dyn 2004; 229: 201-218 DOI: 10.1002/dvdy.10480.
• 23 Smith JC, Price BM, Green JB. et al. Expression of a Xenopus homolog of Brachyury (T) is an immediate-early response to mesoderm induction. Cell 1991; 67: 79-87 DOI: 10.1016/0092-8674(91)90573-h.
• 24 Wilkinson DG, Bhatt S, Herrmann BG.. Expression pattern of the mouse T gene and its role in mesoderm formation. Nature 1990; 343: 657-659 DOI: 10.1038/343657a0.
• 25 Feng X, Cheung JPY, Je JSH. et al. Genetic variants of TBX6 and TBXT identified in patients with congenital scoliosis in Southern China. J Orthop Res 2021; 39: 971-988 DOI: 10.1002/jor.24805.
• 26 Ghebranious N, Blank RD, Raggio CL. et al. A missense T (Brachyury) mutation contributes to vertebral malformations. J Bone Miner Res 2008; 23: 1576-1583 DOI: 10.1359/jbmr.080503.
• 27 Postma AV, Alders M, Sylva M. et al. Mutations in the T (brachyury) gene cause a novel syndrome consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal. J Med Genet 2014; 51: 90-97 DOI: 10.1136/jmedgenet-2013-102001.
• 28 Miettinen M, Wang Z, Lasota J. et al. Nuclear Brachyury Expression Is Consistent in Chordoma, Common in Germ Cell Tumors and Small Cell Carcinomas, and Rare in Other Carcinomas and Sarcomas: An Immunohistochemical Study of 5229 Cases. Am J Surg Pathol 2015; 39: 1305-1312 DOI: 10.1097/PAS.0000000000000462.
• 29 Hsu W, Mohyeldin A, Shah SR. et al. Generation of chordoma cell line JHC7 and the identification of Brachyury as a novel molecular target. J Neurosurg 2011; 115: 760-769 DOI: 10.3171/2011.5.JNS11185.
• 30 Sharifnia T, Wawer MJ, Chen T. et al. Small-molecule targeting of brachyury transcription factor addiction in chordoma. Nat Med 2019; 25: 292-300 DOI: 10.1038/s41591-018-0312-3.
• 31 Cottone L, Cribbs AP, Khandelwal G. et al. Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death. Cancer Res 2020; 80: 4540-4551 DOI: 10.1158/0008-5472.CAN-20-1387.
• 32 Shah SR, David JM, Tippens ND. et al. Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer. Cell Rep 2017; 21: 495-507 DOI: 10.1016/j.celrep.2017.09.057.