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Updated: Jan 23, 2026

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

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Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish

Gianluca D'Agati1, Elena María Cabello1, Karl Frontzek2

  • 1Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland.

Disease Models & Mechanisms
|June 22, 2019
PubMed

Insights

Brachyury protein does not initiate chordoma, a rare cancer. Instead, receptor tyrosine kinases (RTKs) drive tumor formation by disrupting notochord cell differentiation and protein stress pathways.

Area of Science:

  • Oncology
  • Developmental Biology
  • Cancer Genetics

Background:

  • Chordoma is a rare, aggressive cancer originating from notochord remnants.
  • The role of brachyury (TBXT) in chordoma initiation is hypothesized but lacks experimental validation.
  • Identifying key drivers of chordoma is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the in vivo notochord-transforming potential of genes implicated in chordoma.
  • To determine whether brachyury or receptor tyrosine kinases (RTKs) initiate chordoma.
  • To explore potential therapeutic targets for chordoma.

Main Methods:

  • Utilized a zebrafish chordoma model to study gene function in vivo.
  • Assessed the ability of brachyury and specific RTKs (EGFR, Kdr/VEGFR2) to induce notochord hyperplasia.
  • Analyzed the impact of RTK/Ras signaling on notochord differentiation and cellular stress pathways.

Main Results:

  • Brachyury, even with enhanced activity, did not initiate notochord hyperplasia.
  • EGFR and Kdr/VEGFR2 were sufficient to transform notochord cells, indicating their oncogenic potential.
  • Activated RTK/Ras signaling impaired notochord differentiation, including unfolded protein response and ER stress pathways.

Conclusions:

  • Provides the first in vivo evidence against brachyury as a chordoma initiator in the notochord.
  • Suggests activated RTK signaling as a potential initiating event in chordoma development.
  • Highlights endoplasmic reticulum and protein stress pathways as potential therapeutic targets for chordoma.
Keywords:
CancerDanio rerioIn vivo modelsNotochordRTKTBXT

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