About the Project
Heterogeneity in drug response is a confounder to successful cancer treatment. Even within genetically identical populations, cells respond differently to drugs due to factors including stochasticity in gene expression, cell cycle phase/state and the environment. We have been tackling the problem of heterogeneous drug response and resistance using 2D quantitative, single-cell, timelapse imaging of cancer cell lines engineered to express fluorescent reporters to track their cell cycle or…
signalling state. This powerful approach can address how the history and state of a cell determine its response to a given drug and has revealed, e.g., how the CDK inhibitor protein, p21, can determine the outcome of long-term CDK4/6 inhibition and propensity for relapse in lung cancer.
While 2D cell experiments have proven insightful, cancer cells do not grow in rigid environments as monolayers, and we need more realistic models to better quantify drug response. However, imaging 3D cultures over time has proven challenging due to phototoxicity and the time required for 3D imaging. We have developed state-of-the-art light-sheet fluorescence microscope systems employing a single high numerical aperture objective for both light-sheet illumination and detection, called oblique plane microscopes (OPM). These microscopes provide high-speed, low-phototoxicity, light-sheet microscopy on conventional microscope frames and have e.g. been used to achieve 3D imaging of 50 spheroids at 15-minute intervals over days.
We aim to identify drugs that synergise with cell cycle-targeting drugs in cancer treatment. The student will optimise the OPM hardware and develop software pipelines to enable cell cycle responses of 3D cancer spheroids expressing fluorescent cell-state reporters to be tracked and quantified over time to determine how identified drug combinations impact these responses. The student will develop label-free optical coherence tomography (OCT) on the dOPM system to allow low light-dose tracking of cells between the acquisition of fluorescence images. Once synergistic combinations have been identified, the student will determine the mechanism of synergy and optimal drug scheduling. This project would suit a student with a physics, relevant physical sciences or relevant engineering background with a strong interest in optical physics and a strong motivation to apply this to study cancer biology.
To apply for this project please follow the application instructions provided on the LMS website (https://lms.mrc.ac.uk/work-and-study/studentships/lms-4-year-phd-studentships/) and submit an application form by the deadline. 'Registering your interest' below will not be considered an application.
Funding Notes
This studentship covers all tuition fees as well as a tax free stipend amounting to £26,500pa paid directly to the student in monthly instalments.
The funding is available for both Home and Overseas students.
References
- Cutty, S. J. et al. Pro-survival roles for p21(Cip1/Waf1) in non-small cell lung cancer. British Journal of Cancer 2024 1–17 (2024) doi:10.1038/s41416-024-02928-9.
- Crozier, L. et al. CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Mol. Cell 83, 4062-4077.e5 (2023).
- Vuillemenot, L.-A. et al. Wee1 opposes APC/CCdh1 activity to promote S-phase entry. bioRxiv 2025.12.01.691493 (2025) doi:10.64898/2025.12.01.691493.
- Dunsby, C. Optically sectioned imaging by oblique plane microscopy, Optics Express 16 (25), pp. 20306-20316, 2008 doi:10.1364/OE.16.020306
- Sparks, H. et al. High content 3D imaging by dual-view oblique plane microscopy. PNAS Nexus 4, (2025).
- Wang, L. et al. Methods and applications of full-field optical coherence tomography: a review, Journal of Biomedical Optics, 27(5), 050901 (2022) doi: 10.1117/1.JBO.27.5.050901