ZFIN ID: ZDB-PUB-190622-1
Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish
D'Agati, G., Cabello, E.M., Frontzek, K., Rushing, E.J., Klemm, R., Robinson, M.D., White, R.M., Mosimann, C., Burger, A.
Date: 2019
Source: Disease models & mechanisms   12(7): (Journal)
Registered Authors: Burger, Alexa, D'Agati, Gianluca, Mosimann, Christian, White, Richard M.
Keywords: Brachyury, Cancer, Chordoma, In vivo models, Notochord, RTK, Zebrafish
MeSH Terms:
  • Animals
  • Chordoma/enzymology*
  • Chordoma/genetics
  • Fetal Proteins/metabolism*
  • Notochord/enzymology
  • Notochord/pathology
  • Oncogenes
  • Receptor Protein-Tyrosine Kinases/metabolism*
  • T-Box Domain Proteins/metabolism*
  • Zebrafish
PubMed: 31221659 Full text @ Dis. Model. Mech.
The aberrant activation of developmental processes triggers diverse cancer types. Chordoma is a rare, aggressive tumor arising from transformed notochord remnants. Several potentially oncogenic factors have been found deregulated in chordoma, yet causation remains uncertain. In particular, sustained expression of the notochord regulator Brachyury is hypothesized as key driver of chordoma, yet experimental evidence is absent. Here, we apply a zebrafish chordoma model to identify the notochord-transforming potential of implicated genes in vivo We find that Brachyury, including a form with augmented transcriptional activity, is insufficient to initiate notochord hyperplasia. In contrast, the chordoma-implicated receptor tyrosine kinases EGFR and KDR/VEGFR2 are sufficient to transform notochord cells. Aberrant activation of RTK/Ras signaling attenuates processes required for notochord differentiation, including of the unfolded protein response and endoplasmic reticulum stress pathways. Our results provide first in vivo indication against a tumor-initiating potential of Brachyury in the notochord, and imply activated RTK signaling as possibly initiating event in chordoma. Further, our work points at modulating endoplasmic reticulum and protein stress pathways as possible therapeutic avenue against chordoma.