A key mechanism underlying tumour initiation involves the acquisition of a selective advantage by early malignant cells, which outcompete and eliminate neighbouring non-transformed cells. This ‘super-competitive’ behaviour is often linked to increased activity of the oncogene MYCN, which is also associated with neuroblastoma, the most common extra-cranial solid tumour in infants. Neuroblastoma tumours arise during embryonic development, typically at the trunk level, within a multipotent cell population – the neural crest (NC) – that gives rise to the adrenal gland and sympathetic ganglia. We recently established a tractable system that facilitates the temporal dissection of MYCN-driven neuroblastoma initiation. This involves the stepwise differentiation of human embryonic stem cells (hESCs) toward trunk NC and its derivatives (Frith et al. 2018; Frith et al. 2019). To mimic MYCN hyperactivity, we engineered hESCs to overexpress MYCN simultaneously with the fluorescent reporter in a Doxycycline (Dox)-inducible manner. Our preliminary data shows that Dox-inducible elevation of MYCN activity promotes hallmarks of tumourigenesis such as impaired differentiation and increased proliferation.
This PhD project aims to understand how MYCN promotes tumour initiation in trunk NC cells and test the hypothesis that this occurs via the selection of super-competitive cells. We will first examine the mode of competitive cell interactions between MYCN-overexpressing cells and their normal isogenic counterparts. To this end we will monitor interactions of fluorescently-labelled wild-type and MYCN-overexpressing cells in mosaic cultures using time-lapse imaging at different time points of NC differentiation (Price et al. 2021). We will then define the mechanisms underlying the selection of super-competitive cells and elimination of their neighbours using a combination of transcriptome analysis, pharmacological inhibition of candidate signalling pathways and electrophysiology. Finally, we will integrate findings from the above experiments within an established computational framework for cell competition to obtain a quantitative, predictive model for neuroblastoma initiation and its clonal evolution.
This is a truly collaborative project between four research groups with complementary expertise and background in a diverse range of techniques/fields and thus it will provide in-depth training in:
Human stem cell and developmental biology (Anestis Tsakiridis, https://www.tsakiridislab.com/, Twitter: @a_tsakiridis), cell competition and live imaging (Ivana Barbaric, https://www.sheffield.ac.uk/biosciences/people/academic-staff/ivana-barbaric, Twitter: @IvanaBarbaric3), mathematical modelling (Alex Fletcher, https://alexfletcher.github.io/about/, Twitter: @AlexGFletcher) and
neuroscience/neurophysiology (Matthew Livesey,
https://www.sheffield.ac.uk/medicine/people/neuroscience/matthew-livesey).
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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