The zebrafish as a model for Epithelioid hemangioendothelioma (EHE)

Epithelioid hemangioendothelioma (EHE) is a rare sarcoma of the endothelial cells lining the blood vessels. 90% of cases show a translocation resulting in the TAZ-CAMTA1 fusion protein, and 10% have a translocation resulting in the YAP1-TFE3 fusion. Although EHE is rare, it is driven by constitutively activated YAP/TAZ signalling. Hippo is a vital pathway involved in many cancers, hence any breakthroughs here may also have significant implications for other cancers. As there are no specific treatments for EHE, there is a great need for in vivo models.

I aimed to create a TAZ-CAMTA1 and a YAP1-TFE3 zebrafish model to further characterise EHE. I initially created a TAZ-CAMTA1 model but found that although TAZ/CAMTA1 target genes were induced, expression levels of the oncogene were low, and unexpectedly, transcription stopped early in CAMTA1, exon 15. In an attempt to promote tumour formation in this line, CDKN2 mutations were induced in this background, as these are the most common secondary mutations in EHE disease.
However, few tumours arose from this additional mutation. One potential issue was that the TAZ- CAMTA1 gene is extremely long, which may impair high levels of expression. Therefore, a much shorter YAP1-TFE3 model was created to overcome these issues. However, there were also problems with this as it was found, unexpectedly, that YAP1-TFE3 expression levels appeared to be reduced upon activation. In addition, I generated an alternative version of TAZ-CAMTA1 to attempt to address the poor expression encountered during this work, but this did not appear to solve these issues. However, this was not conclusive, as RNAseq was not performed on these transgenics. It can be concluded that the expression of these transgenes is surprisingly difficult, and the use of xenotransplants may be the way forward to create a preclinical model to test potential disease-modifying drugs, for treatment of EHE.