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

Dis Model Mech. 2019 Jul 16;12(7):dmm039545. doi: 10.1242/dmm.039545.

Abstract

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 to be deregulated in chordoma, yet causation remains uncertain. In particular, sustained expression of TBXT - encoding the notochord regulator protein brachyury - is hypothesized as a key driver of chordoma, yet experimental evidence is absent. Here, we employ 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 (RTKs) EGFR and Kdr/VEGFR2 are sufficient to transform notochord cells. Aberrant activation of RTK/Ras signaling attenuates processes required for notochord differentiation, including the unfolded protein response and endoplasmic reticulum stress pathways. Our results provide the first in vivo evidence against a tumor-initiating potential of Brachyury in the notochord, and imply activated RTK signaling as a possible initiating event in chordoma. Furthermore, our work points at modulating endoplasmic reticulum and protein stress pathways as possible therapeutic avenues against chordoma.

Keywords: Cancer; Danio rerio; In vivo models; Notochord; RTK; TBXT.

Publication types

  • Research Support, Non-U.S. Gov't

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

Substances

  • Fetal Proteins
  • T-Box Domain Proteins
  • Receptor Protein-Tyrosine Kinases
  • Brachyury protein