Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish
Open Access
- 1 January 2019
- journal article
- research article
- Published by The Company of Biologists in Disease Models & Mechanisms
- Vol. 12 (7)
- https://doi.org/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.Funding Information
- Schweizerischer Nationalfonds zur F?rderung der Wissenschaftlichen Forschung (139093)
- FP7 People: Marie-Curie Actions (PCIG14-GA-2013-631984)
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