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

• Main Authors: Gianluca D'Agati, Elena María Cabello, Karl Frontzek, Elisabeth J. Rushing, Robin Klemm, Mark D. Robinson, Richard M. White, Christian Mosimann, Alexa Burger
• Format: Article
• Language: English
• Published: The Company of Biologists 2019-07-01
• Series: Disease Models & Mechanisms
• Subjects: Notochord; TBXT; RTK; Cancer; Danio rerio; In vivo models
• Online Access: http://dmm.biologists.org/content/12/7/dmm039545
• ISSN: 1754-8403; 1754-8411

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.