Identification of Regulating Mechanisms of TBXT Gene Expression in Chordoma

• Applicants: Professor Dr. Thomas Barth; Dr. Kevin Mellert
• Subject Area: Pathology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441595227

Chordomas are rare malignant bone tumors. Due to their low incidence, chordomas are part of the so-called orphan diseases. Chordomas arise along the spine mainly in the clivus or the sacrum. Therapy of choice is the complete resection whenever possible. Chordomas do not respond to conventional chemo- or radiotherapy.We have established the worldwide largest panel of chordoma cell lines and have a tumor bank of more than 50 chordomas with clinical follow-up. In recent studies, we showed that chordomas have a HOX gene expression profile dependent on whether they arise in the clivus or the sacrum. These genes play an important role in the development of the anterior-posterior body axis. The differential expression points to a different biology of clival and sacral chordomas. In first pilot studies, we show that an inhibition of the HOX proteins induces apoptosis in chordoma cell lines. Therefore, HOX proteins may serve as possible targets for the therapy of chordomas.Brachyury has a key role in the biology of chordomas. The results of our first analyses suggest that Brachyury is regulated by miRNAs. Hence, this pathway will be studied in details in order to become able to modulate Brachyury expression. Our well defined collection of chordoma cell lines and tumor tissues are the basis to address these issues. All methods and techniques needed are established in our institute including classical cell culture (stimulation and inhibition of cellular growth and proliferation and mouse xenografting), molecular biological approaches (transfections, measurements of cell proliferation and apoptosis, Western blots, immunohisto-/cytology, quantitative real-time PCR, cell cycle analysis), and biostatistical analyses (annotation of mutations and comparative studies of methylation and expression of genes).This is the first study that aims at integrating in vitro and in situ data to gain deeper insights into the molecular biology of chordoma using an established cell line collection and a tumor bank. The long-term aim is to identify novel targets for therapy of this rare disease by regulation of the protein Brachyury as a keyfactor in chordomas biology.

• DFG Programme: Research Grants