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


D'Agati, Gianluca; Cabello, Elena María; Frontzek, Karl; Rushing, Elisabeth J; Klemm, Robin; Robinson, Mark D; White, Richard M; Mosimann, Christian; Burger, Alexa (2019). Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish. Disease Models & Mechanisms, 12(7):dmm039545.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:1 July 2019
Deposited On:15 Jan 2020 15:44
Last Modified:30 Mar 2020 13:53
Publisher:The Company of Biologists Ltd.
ISSN:1754-8403
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1242/dmm.039545
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P3_139093
  • : Project TitleDeciphering the control of lateral mesoderm cell fates in zebrafish

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