Investigating KAT2A as a novel therapeutic target in neuroblastoma

The Pina lab is looking for a highly-motivated, technically-able and independent-thinking candidate to undertake a PhD project researching the role of histone acetyl-transferase KAT2A in neuroblastoma.

The project will be supervised by Dr Cristina Pina (https://www.brunel.ac.uk/people/cristina-pina), in collaboration with Professor Arturo Sala (https://www.brunel.ac.uk/people/auturo-sala).

The Pina lab specialises in epigenetic and transcriptional regulation of normal and malignant stem cell fate decisions, and has an interest in the role of histone acetyl-transferase KAT2A in cancer. The group has previously characterised KAT2A as a vulnerability in Acute Myeloid Leukaemia (Tzelepis et al, 2016), its loss resulting in progressive depletion of leukaemia stem cells (Domingues et al, 2020). KAT2A exerts its effects through 2 distinct complexes, SAGA and ATAC, which respectively control cell differentiation and biosynthetic programmes (Arede and Pina, 2021).

The Sala group has been involved in neuroblastoma research for over 20 years, contributing to the identification of oncogenes and tumour suppressor genes relevant to this cancer (Chaika et al, 2009; Chaiwatanasirikul and Sala, 2011; Corvetta et al, 2013; Dvorkina et al, 2016).

Neuroblastoma is the most common solid tumour in children under the age of 5. It has a poor overall 5-year survival of <75%, which drops to <60% in high-risk disease. High-risk disease is associated with amplification of the MYCN gene, which has been shown to partner KAT2A during development of the nervous system. Preliminary data from our group suggests that inhibition of KAT2A kills neuroblastoma cells with MYCN amplification, and may constitute a novel therapeutic strategy in neuroblastoma.

In this project, you will use chemical and genetic ablation of KAT2A, and of components of SAGA and ATAC complexes, to dissect the cellular and molecular mechanisms by which KAT2A complexes sustain neuroblastoma cells. You will use 2D and organoid-culture systems and employ transcriptional and chromatin analysis tools to analyse MYCN amplified and non-amplified cell lines and primary neuroblastoma samples, and to target differentiated and stem-like neuroblastoma cells.

If you are a keen lab worker and passionate about cancer research, we would like to hear from you. To apply, you will need to have a First or Upper Second-class BSc (Hons) degree or equivalent in Biology, Biomedical Sciences, Natural Sciences, Life Sciences, Genetics, Biochemistry or similar areas, and previous lab experience.

An MSc qualification is desirable but not essential. You will have excellent oral and written communication skills, and demonstrate the capacity to autonomously research, synthesise and critically evaluate relevant literature. You should be able to work independently and as part of a team, and have a dedicated and flexible approach to work.

References:

• Arede and Pina (2021) doi: 10.1016/j.exphem.2020.10.003
• Chaika et al (2009) doi: 10.1093/jnci/djp063
• Chaiwatanasirikul and Sala (2011) doi: 10.1038/cddis.2011.99
• Corvetta et al (2013) doi: 10.1074/jbc.M113.454280
• Domingues et al (2020) doi: 10.7554/eLife.51754
• Dvorkina et al (2016) doi: 10.1158/1078-0432.CCR-15-2081
• Tzelepis et al (2016) doi: 10.1016/j.celrep.2016.09.079

How to apply

If you are interested in applying for the above PhD topic please follow the steps below:

1. Contact the supervisor by email or phone to discuss your interest and find out if you woold be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
2. Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
3. Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.

Good luck!

This is a self funded topic

Brunel offers a number of funding options to research students that help cover the cost of their tuition fees, contribute to living expenses or both. See more information here: https://www.brunel.ac.uk/research/Research-degrees/Research-degree-funding. The UK Government is also offering Doctoral Student Loans for eligible students, and there is some funding available through the Research Councils. Many of our international students benefit from funding provided by their governments or employers. Brunel alumni enjoy tuition fee discounts of 15%.

Meet the Supervisor(s)

Cristina Correia Antunes Pina - I am a clinically-trained research scientist working in the field of cancer epigenetics. I am fascinated by the mechanisms through which cells diversify their molecular composition, and consequently vary their morphology and their function, to make organs, regenerate tissues, and produce tumours. While some of those diversification mechanisms rely on genetic mutations, others explore the way in which cells read their genes to produce the RNA and proteins that underlie cell function. The latter are referred to as epigenetic mechanisms. My research is focused on understanding and manipulating epigenetic mechanisms to alter cell identity, and in particular, it aims to probe their role in cancer evolution in an attempt to unveil new therapies.

Arturo Sala - Trained in Biochemistry and Cellular Biology at the University of Rome and the Italian National Institute of Health, I completed a PhD in Biochemistry at the University of Rome “La Sapienza” on the topic of DNA and RNA methylation in relation to muscle cell differentiation.  After a short postdoctoral training in the National Institute of Health in Rome, I won an international post-doctoral fellowship from the Italian Association for Cancer Research (AIRC) and moved to the Kimmel Cancer Institute, Thomas Jefferson University Philadelphia. Working in the laboratory of Prof. Bruno Calabretta, I was the first to characterize the transcription factor and oncoprotein B-MYB and establish its relationship with key tumour suppressor genes, such as p53 and retinoblastoma family members.  In 2001 I was recruited by the UCL Institute of Child Health as Senior Lecturer and later promoted to Reader. In UCL I continued to pursue the study of oncogenic transcription factors in the context of neuroblastoma, a childhood tumour affecting the peripheral nervous system. I was appointed Professor of Translational Cancer Research and Deputy Director of the Brunel Institute of Cancer Genetics and Pharmacogenomics in September 2011. In 2016 I joined the Synthetic Biology Theme in the Institute of Environment, Health and Societes. 

Related Research Group(s)

Inflammation Research and Translational Medicine - Driving scientific innovation and discovery for diagnosis, treatment, and management of cardiovascular disease, inflammatory and immune disorders, microbial resistance, and cancer.