E-MTAB-7349 - Receptor Tyrosine Kinase pathway activation is sufficient to trigger chordoma in zebrafish

Status
Submitted on 28 June 2016, last updated on 29 November 2018, released on 1 December 2018
Organism
Danio rerio
Samples (6)
Protocols (4)
Description
Oncogenic transformation of individual cell fates by developmental signaling cascades and transcription factors triggers diverse cancer types. Chordoma is a rare, aggressive tumor arising from transformed notochord remnants. Various potentially oncogenic factors have been found deregulated in chordoma and its metastases, yet clear causation remains uncertain. In particular, expression of the notochord-controlling transcription factor Brachyury is hypothesized as key molecular driver in chordoma formation, yet an in vivo model to causally test its oncogenic potential in the notochord is missing. Here, we apply a zebrafish model of chordoma onset to identify the notochord-transforming potential of tumor-implicated candidate genes in vivo. We find that overexpression of human and zebrafish Brachyury, including a version with augmented transcriptional activity, is insufficient to initiate notochord hyperplasia in vivo. In contrast, the repeatedly chordoma-implicated receptor tyrosine kinase (RTK) genes EGFR and KDR/VEGFR2 are sufficient to transform developmental notochord cells, akin to direct activation of Ras. Analysis of transcriptome and sub-cellular organization from transformed notochords suggests that aberrant activation of RTK/Ras signaling attenuates processes required for the differentiation of notochord cells. Taken together, our results provide first in vivo indication for a lack of tumor-initiating potential of Brachyury expression in the notochord, and suggest activated RTK signaling as potent hyperplasia-initiating event in chordoma.
Experiment types
RNA-seq of coding RNA, case control design
Contact
MINSEQE
Exp. designProtocolsVariablesProcessedSeq. reads
Files
Investigation descriptionE-MTAB-7349.idf.txt
Sample and data relationshipE-MTAB-7349.sdrf.txt
Links