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

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

Author information

1
Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland.
2
Institute of Neuropathology, University Hospital Zürich, 8091 Zürich, Switzerland.
3
SIB Swiss Institute of Bioinformatics, University of Zürich, 8057 Zürich, Switzerland.
4
Cancer Biology & Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland alexa.burger@imls.uzh.ch.

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

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