PhD

Manchester PhD

This four year PhD (2019-2022) was undertaken at the Division of Developmental Biology and Medicine at the University of Manchester. The work was undertaken in Dr Valerie Kouskoff’s lab and was fully funded by the EHERCC.

The aim of the research was to develop a model of EHE, which could then be used to investigate various aspects of EHE biology. The model utilised mouse embryonic stem cells, which were differentiated to endothelial cells. TAZ-CAMTA1 expression was then induced in these endothelial cells, allowing its function to be investigated in the same cell-of-origin as EHE tumours in humans. It was hoped that the research using this model would uncover previously unexplored mechanisms of EHE development, which could lead to the identification of potential therapeutic targets and novel treatment options for EHE patients.

Investigations using the stem cell-based model have revealed that TAZ-CAMTA1 expression causes a large amount of DNA damage in endothelial cells. DNA damage often occurs in cells, and is usually repaired without consequence by one of multiple DNA repair pathways. In TAZ-CAMTA1 expressing endothelial cells, the large amount of damage overwhelms these repair mechanisms, and often goes unrepaired. The research team discovered that, in many TAZ-CAMTA1 expressing cells, this DNA damage caused cells to became trapped in the cell cycle and ultimately enter a state of senescence. This is a state in which the cells are dormant, and cannot divide but also do not die. Senescent cells can accumulate in a tumour, and project data suggests that this could represent the indolent, slow-growing tumours many EHE patients present with.

Of particular note was the fact that TAZ-CAMTA1 appeared to damage the Homologous Recombination pathway, the main repair pathway in cells, leading to more error-prone pathways attempting to repair the DNA damage and hyper-transcription. The teams hypothesised that this leaves cells vulnerable to further genetic mutations occurring, which may then allow cells to bypass the barrier of senescence and induce uncontrollable proliferation. This could be the reason some EHE tumours suddenly become more aggressive and metastasise. After completion of the PhD the team were investigating if using PARP inhibitors, drugs to inhibit some of the proteins involved in the onset of DNA damage or senescence-bypass, can induce the death of TAZ-CAMTA1 expressing endothelial cells. Some of these inhibitors are already used or in clinical trial for treating other types of cancer. If any of these prove successful, these drugs could become available for EHE patients in the future after further testing.

Dr Valerie Kouskoff has led her laboratory at the School of Medical Sciences at the University of Manchester since 2016. Interest in the Hippo pathway effectors YAP and TAZ in normal regulation and their chromosomal translocations leading to vascular tumours led to her interest in EHE

Dr Valerie Kouskoff heads a research group at the University of Manchester, UK in the Division of Developmental Biology and Medicine. She did her PhD in Strasbourg, France and post-doctoral training in Denver, USA. After this training in basic and applied immunology, she joined the laboratory of Professor Keller at Mount Sinai Hospital in New York, USA before starting her own programme of research at the Cancer Research UK Manchester Institute, then in 2016 moved to the University of Manchester. Her group has focused on further understanding the molecular and cellular mechanisms underlying the formation of the cardiovascular system. Over the years, her group has made seminal contributions in defining how this system is established during embryonic life. Using in vitro and in vivo models, one major aim of her team focused on the identification of novel regulators of haematopoietic and endothelial specification and how those are disrupted in malignancies and diseases.

Emily Neil (right) joined Dr Kouskoff’s lab at the start of 2019 to begin her PhD studies, developing a stem-cell based model for investigating EHE development and the consequences of TAZ-CAMTA1 expression. She was awarded her PhD in March 2023. She has since moved to a postdoctoral position at the University of Oxford, where she will be studying childhood leukaemia development.

We want to thank Emily and Dr Kouskoff for their excellent work on EHE undertaken in Manchester.