Psaila Group: How does altered mechanobiology of the cancer microenvironment perturb cell cycle controls and cause genome instability?

About the Research

The research in our laboratory focusses on discovery of targetable disease mechanisms in a group of chronic blood cancers called myeloproliferative neoplasms (MPNs). Specifically, we focus on how and why patients who initially present with indolent cancer progress to advanced-stage MPN. A central hallmark in this progress is the development of severe bone marrow fibrosis (myelofibrosis), which leads to bone marrow failure, inadequate production of blood cells and a chronic inflammatory state. The severe inflammation and fibrosis in the bone marrow mediate the severe clinical features suffered by patients, and also fuel cancer evolution. Therefore myelofibrosis is often held as an exemplar for how the tumour microenvironment can play an instructive role in determining cancer evolution and clinical outcomes.

This project will focus on understanding how the development of fibrosis alters the mechanobiology of the bone marrow microenvironment, and in turn how this influences cell cycle controls and genome stability of normal and malignant blood stem cells, and their progeny. We are also interested in understanding how alterations in the cancer microenvironment fuel the competitive advantage for the malignant clone – and in particular how this may contribute to poor outcomes for patients with myelofibrosis who undergo stem cell transplantation. Patients with myelofibrosis who undergo allograft have substantially poorer outcomes due to higher rates of secondary graft failure/relapse than those with other blood malignancies where there is less bone marrow fibrosis and inflammation, suggesting that the myelofibrotic microenvironment is hostile for the healthy donor cells to survive and regenerate healthy blood production.

This will involve using a number of state-of-the-art tools and experimental platforms that we have recently developed - including human bone marrow organoids (see Khan et al, Cancer Discovery 2023 and Olijnik et al, Nature Protocols 2024) and a new in vivo model developed in collaboration with the Nerlov lab where we are able to induce a cancer driver mutation only on a subset of blood stem cells. This enables us to study changes to the bone marrow niche during controlled clonal expansion without irradiation and transplant for the first time, better mimiking how cancers evolve in humans.

I am also an active clinician, looking after patients with chronic myeloid blood cancers and leading a number of clinical trials, with a particular focused on emerging immunotherapies. The research in our lab has a strong translational focus, largely inspired by challenges faced by patients in the clinic and looking to uncover novel aspects of biology that may help ameliorate clinical challenges. We aim to generate biological insights, experimental tools and research outputs that are widely impactful, resulting in high-impact publications, patents and excellent training opportunities for scientists. Our lab ethos is focused on creating a positive nad collaborative research environment in which each individual leads a project but works collaboratively and an ability to work independently and think creatively.

Full list of publications can be found here:

https://www.ncbi.nlm.nih.gov/myncbi/beth.psaila.1/bibliography/public/

And more details are on this website:

https://www.rdm.ox.ac.uk/people/bethan-psaila

Training Opportunities

I am highly committed to training and mentorship. My philosophy in running a research group has been to create an environment that leverages the strengths of individual resaerchers, supporting their career goals while maximising the collective impact and outputs on the group. This approach has been highly sucessful, with mentees/alumni from the group have been highly successful in securing independent funding including personal fellowships, group leader positions in academia and positions in industry and publishing, with excellent publication track records. These efforts were recognised by the RDM-WIMM Sir Andrew McMichael Award for Excellent Supervision and Mentorship in 2021.

This project will offer excellent training opportunities. We use a wide range of experimental techniques including single cell multi-omics, mouse models, cell culture, genome engineering, working with primary patient cells and advanced genetic models in addition to complex 3D models (organoids) to model disease, develop and test therapies. All students work with a dedicated postdoctoral researcher, providing excellent day-to-day supervison and mentorship. Students will be offered a choice of projects to ensure that it fits with their interests and skills, and will be joining a happy and collegiate group of researchers, who work in close collaboration with several neighboring labs in the WIMM and wider oxford ecosystem. Although based in the WIMM I am also affiliated with the Oxford Ludwig Cancer Research Institute (https://www.ludwig.ox.ac.uk/) and students will benefit from training resources and collaborations between both institutes.

We are fortunate to be a well funded lab, and I encourage trainees to attend national and international conferences to present their work and develop their own research network. I spent >6 years in the US during my training, so have a wide network of friends and collaborators and encourage collaborative projects and placements to learn new skills and experiences.

Given our focus on molecular biology and single cell approaches, many in our team are fluent in computational biology as well as ‘wet lab’ techniques, and we support trainees to attend dedicated computational training courses where appropriate.

In addition to many academic collaborations, we also work closely with industry. Together with Adam Mead who runs a neighboring lab, I co-founded a spin-out company called Alethiomics, part of which is embedded in the lab, and we have filed several patents on recently developed technologies. These links offer excellent training for individuals interested in translational science, relevant for future careers in both academia and industry.

Alumni from the group have an excellent track record with securing independent fellowships, group leader positions and jobs in industry, publishing and academic core facilities.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Additional Supervisors

Publications