Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.
Our results provide the first <i>in vivo</i> evidence against a tumor-initiating potential of Brachyury in the notochord, and imply activated RTK signaling as a possible initiating event in chordoma.
To evaluate the characteristics of vascular and tumor cells in chordoma, we first analyzed the expression of VEGF receptor (VEGFR) 1, VEGFR2, CD34, and Brachyury in a cell line and 54 tumor tissues.
The GSK3β inhibitor (AR) decreased brachyury expression and suppressed the growth and survival of the chordoma cells, possibly via regulation of the Wnt/β-catenin signaling pathway.
Expression of PI3K/Akt pathway genes was upregulated in Brachyury high-expression tumors, and suppression of PI3K signaling led to reduced Brachyury expression and inhibition of cell growth in the U-CH2 chordoma cell line.
We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative IC<sub>50</sub>s correlate with the unique ability of afatinib to promote degradation of EGFR and brachyury, an embryonic transcription factor considered a key driver of chordoma.
All 8 cases were positive for brachyury, whereas there was no nuclear SMARCB1/INI1 expression in 4 of the 8 cases, including the poorly differentiated chordoma.
To call attention to this association, we present a brachyury-immunopositive chordoma occurring in the skull base of a 2-month-old male infant who was later realized to have metastases to the subcutaneous tissues and lungs, as well as rhabdomyoma of the heart and renal cysts/angiomyolipomas, that is, characteristic features of the TS complex.
Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.
Chor-IN-1 displays genomic identity to the tumor of origin and has morphological features, growth characteristics and chromosomal abnormalities typical of chordoma, with expression of brachyury and other relevant biomarkers.
Recently, the single nucleotide polymorphism (SNP) rs2305089 in the T (brachyury) gene was strongly associated with sporadic chordoma development, but its clinical utility is undetermined.
Recent advances in the understanding of the molecular events that contribute to the development of chordomas are promising; the most novel finding being the identification of brachyury in the disease process.
The second case was a quickly fatal clival tumor in a 2-year-old boy: This tumor was morphologically undifferentiated and raises the problem of differential diagnosis between an MRT, a malignant myoepithelial tumor, or an undifferentiated chordoma due to the location and the expression of brachyury.
Cells were cultured for more than 30 passages and the expression of the chordoma cell marker brachyury was monitored using both immunohistochemistry and Western blot.
Known for decades as a main regulator of notochord formation, Brachyury has recently gained interest as a biomarker and causative agent of chordoma, and therefore as a promising therapeutic target.
The brachyury gene is believed to be one of the key genes involved in the pathogenesis of chordoma, a rare primary bone tumor originating along the spinal column or at the base of the skull.