PT  - JOURNAL ARTICLE
AU  - D'Agati, Gianluca
AU  - Cabello, Elena María
AU  - Frontzek, Karl
AU  - Rushing, Elisabeth J.
AU  - Klemm, Robin
AU  - Robinson, Mark D.
AU  - White, Richard M.
AU  - Mosimann, Christian
AU  - Burger, Alexa
TI  - Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish
AID  - 10.1242/dmm.039545
DP  - 2019 Jul 01
TA  - Disease Models & Mechanisms
PG  - dmm039545
VI  - 12
IP  - 7
4099  - http://dmm.biologists.org/content/12/7/dmm039545.short
4100  - http://dmm.biologists.org/content/12/7/dmm039545.full
SO  - Dis Models Mech2019 Jul 01; 12
AB  - 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.