The biophysics of cell division in tumours

1) Brief description of the context of the research including potential impact
We are developing methods for imaging the microstructure of human tissue at high resolution and in three dimensions, across large tissue samples. Cells are often densely packed within tumours, and form complex three-dimensional patterns that interact with blood vessel networks. Moreover, alongside the extracellular matrix, the composition of cells can cause the mechanical properties of tumours to differ significantly from those of the normal surrounding tissue. This effect is utilized in the clinical identification of tumours - for example the appearance of a hard lump in breast tissue - but its cause is incompletely understood. To investigate the genetic and molecular origins of increased mechanical stiffness in tumours, we are combining novel imaging techniques (such as high-resolution episcopic microscopy (HREM), magnetic resonance imaging (MRI) and atomic force microscopy (AFM)) with mathematical modelling to provide a clearer picture of the biophysics and biomechanics of cancer.
2) Aims and Objectives
-The specific objectives are to:
The main aim of this project is to optimise the imaging of mitotic cells within tumours using High-Resolution Episcopic Microscopy (HREM). This currently has a resolution of up to ~0.8microns in x-y and in z (sections are typically 1micron in depth). Importantly, using HREM, we also expect to be able to use a range of fluorescent markers to image mitotic events in their native 3D environment deep in tumours.
For this analysis, the student will: i) de-paraffinise tumours that are positive/negative for oncogenic Ras-ERK signalling; ii) stain tumours for markers of the DNA, cortex/membrane, spindle and ECM, iii) dehydrate tumours and embed them in resin, iv) mount and image the tissue using HREM. This procedure is complex and will require optimisation for imaging individual cells, although we have preliminary data showing individual nuclei can be discerned in tissue samples.
Once we have imaged mitotic events inside tumours, we will use microfabrication methods to recapitulate these environments in the lab to determine how the physical conditions found in real tumours likely influence mitosis. Parameters we will replicate will include: i) crowding, ii) ECM organisation, iii) interphase cell shape, iv) adhesive contact area.
Finally, we aim to be able to process tumours for imaging prior to embedding. This will enable us to use new methods (e.g. optical coherence elastography) to measure the mechanical properties of the tissue, and to compare this mechanical profile with cell shape information and, ultimately, with local genetic information. These data will also be used to parameterise mathematical models of tumour biomechanics.

3) Novelty of Research Methodology
This PhD studentship is part of the International Alliance for Cancer Early Detection (ACED).

4) Alignment to EPSRC's strategies and research areas
The project is mainly linked to the theme Artificial intelligence and robotics since we will mainly use machine learning (we aim to find imaging-based biomarkers) to conduct our research. It also involves healthcare technologies as we plan to improve cancer early detection. This early cancer detection approach is critical as it will increase patient survival and reduce the suffering of patients.

5) Any companies or collaborators involved
N/A

The critical mass of scientists and engineers that i4health will produce will ensure the UK's continued standing as a world-leader in medical imaging and healthcare technology research. In addition to continued academic excellence, they will further support a future culture of industry and entrepreneurship in healthcare technologies driven by highly trained engineers with deep understanding of the key factors involved in delivering effective translatable and marketable technology. They will achieve this through high quality engineering and imaging science, a broad view of other relevant technological areas, the ability to pinpoint clinical gaps and needs, consideration of clinical user requirements, and patient considerations. Our graduates will provide the drive, determination and enthusiasm to build future UK industry in this vital area via start-ups and spin-outs adding to the burgeoning community of healthcare-related SMEs in London and the rest of the UK. The training in entrepreneurship, coupled with the vibrant environment we are developing for this topic via unique linkage of Engineering and Medicine at UCL, is specifically designed to foster such outcomes. These same innovative leaders will bolster the UK's presence in medical multinationals - pharmaceutical companies, scanner manufacturers, etc. - and ensure the UK's competitiveness as a location for future R&D and medical engineering. They will also provide an invaluable source of expertise for the future NHS and other healthcare-delivery services enabling rapid translation and uptake of the latest imaging and healthcare technologies at the clinical front line. The ultimate impact will be on people and patients, both in the UK and internationally, who will benefit from the increased knowledge of health and disease, as well as better treatment and healthcare management provided by the future technologies our trainees will produce.

In addition to impact in healthcare research, development, and capability, the CDT will have major impact on the students we will attract and train. We will provide our talented cohorts of students with the skills required to lead academic research in this area, to lead industrial development and to make a significant impact as advocates of the science and engineering of their discipline. The i4health CDT's combination of the highest academic standards of research with excellent in-depth training in core skills will mean that our cohorts of students will be in great demand placing them in a powerful position to sculpt their own careers, have major impact within our discipline, while influencing the international mindset and direction. Strong evidence demonstrates this in our existing cohorts of students through high levels of conference podium talks in the most prestigious venues in our field, conference prizes, high impact publications in both engineering, clinical, and general science journals, as well as post-PhD fellowships and career progression. The content and training innovations we propose in i4health will ensure this continues and expands over the next decade.