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.