MRC DiMeN Doctoral Training Partnership: Who shakes hands with the enemy? Discovering which subsets of mesenchymal stromal cells support acute lymphoblastic leukaemia (ALL) cell growth in the bone marrow.

This project offers a PhD student the opportunity to work with Professor Adele Fielding, a clinician-scientist who studies leukaemia in the lab and in the clinic together with a Professor Paul Genever, a biologist who focuses on mesenchymal stromal cell and skeletal biology. The student will help to unpick how stromal cells become ‘cancer-associated fibroblasts’ (CAF), support leukaemia cells and afford them protection from chemotherapy1. The overall goal in understanding this relationship is to interrupt the connections between cancer cells and their cellular support systems in order to treat leukaemia without chemotherapy. 

The scientific aim of the project offered is to define the distinct genetic and functional identity of the mesenchymal stromal cell subpopulation(s) which support leukaemia. Modelling the stromal cell to CAF transition is well-established in the Fielding lab using chemotherapy-exposure, co-culture with leukaemia cell lines, patient-derived xenografts and primary patient leukaemia cells. In order to determine which from among a number of distinct MSC subpopulations previously identified by the Genever lab2 can become CAF after exposure to ALL cells, the student will use immunofluorescence microscopy, cytokine bead arrays and RQ PCR as read-outs. Next, to understand the genetic determinants of which subpopulations of MSC can become CAF, the student will analyse bulk and singe cell RNA sequencing data generated by both labs to correlate the functional characteristics determined above with relevant gene expression profiles. Finally, in order to dissect the precise mechanisms by which subpopulations of MSC support leukaemia, the student will design mechanistic studies to confirm the findings e.g. CRISPR-Cas9 knockouts, antibody blocking experiments. A bone marrow organoid model3 is also available within Fielding lab for the mechanistic work.

The research question in this project is embedded within the Fielding team’s overall goal of ensuring that patients with acute lymphoblastic leukaemia receive ‘precision medicine’ treatment approaches relevant to their age and the genetic subtype of disease, ultimately substituting ‘chemotherapy for all regardless of age/disease subtype’ with a more nuanced approach which will involve interrupting the connections between cancer cells and their support systems.

The student will benefit from an extremely positive, collaborative research culture primarily based in the Centre for Blood Research at the University of York and close supervision by two experienced supervisors with overlapping but distinct skills and interests. Career progression and acquisition of generic skills of students is taken very seriously within a supportive but professional environment. Students play a full role in the labs including presentations to team members, writing manuscripts and conference attendance to present data. Day-to-day help and supervision from experienced post-doctoral scientists is available. The renowned Bioscience Technology Facility at the University of York provides access to and training on a wide number of state-of-the-art technologies to be used in the project (e.g. imaging and cytometry, genomics, molecular interactions, protein work). The facility is run by experts who offer wonderful courses and specific training to allow the student to achieve competence to use the equipment without supervision.

Adele Fielding:

• https://www.hyms.ac.uk/about/people/adele-fielding
• https://www.york.ac.uk/news-and-events/news/2023/research/centre-blood-research/

Paul Genever: 

• https://www.york.ac.uk/biology/research/developmental-biology/paul-genever/
• https://www.geneverlab.info/

Twitter (X)

@adelekfielding

@paulgenever

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: https://www.dimen.org.uk/blog 

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply