Zebrafish Model

Zebrafish Model

In July 2018 the EHERCC contracted with the University of Sheffield to develop a zebrafish model of EHE. The project is led by Dr Fredericus van Eeden at The Bateson Centre at the University of Sheffield, with Eleanor Markham undertaking the painstaking work.

The zebrafish is an animal that just like mice, can be used to “recreate” human diseases. Such models can then be used to understand the disease better, and perhaps identify and test treatments. The zebrafish has unique advantages, as its embryo develops rapidly; within 5 days a complete larval fish is formed that can feed independently and do everything needed to survive and grow up. In addition, it develops outside the mother and is transparent. Therefore, many processes can be followed in minute detail, for instance blood vessel formation and maintenance, which is highly relevant for EHE.

The primary research goal is to develop a zebrafish model of EHE. The team are working to express TAZ-CAMTA1 and YAP-TFE3, which are fundamental to the onset of EHE,  in the blood vessels of the zebrafish. This has so far been difficult; however, they have recently made clear progress using a molecular switch system. Using a technology that analyses gene expression of all genes across the genome (RNAseq), the team have seen activation of an EHE signature gene set (“the Sealy signature”) in their fish.

Although this is only a first step, and we think further work on increasing TAZ-CAMTA1 expression levels needs to be done, we have started raising fish which will have TAZ-CAMTA1 activated in their blood vessels. In addition, we have targeted another gene,  CDKN2, in some of these fish, which has been show to promote tumour progression in humans. In the coming year we hope to analyse these fish for the formation of EHE-like tumours. If this is successful, we can start using our fish as an accessible model to study the behaviour of these tumours and in the further future as a way to do preclinical testing of treatments.

Dr Fredericus van Eeden (left) is the joint PI of the zebrafish project, and is a Senior Lecturer at the School of Biosciences of the University of Sheffield. The other PI is Dr Robin Young, clinical oncologist based at Weston Park Hospital in Sheffield and a member of the Charity’s advisory Board.

Eleanor Markham (right) is the MPhil student who has been undertaking this painstaking research over the past four plus years.