Accelerating our ability to understand and target complexity and heterogeneity in cancer through automated imaging of 3D cancer models including patient derived organoids

Drug resistance is a major challenge for cancer therapy, arising from heterogeneous cellular behaviours within tumours, where initially identical clonal cells can mutate and adapt to diverse microenvironments. This complexity is rarely addressed in standard assays that typically measure the average response of cell populations in highly artificial contexts and fail to account for outlier cells that may drive drug resistance. There is increasing interest in more complex 3D tissue models, such as patient-derived organoids (PDO) that better recapitulate the complexity of the in vivo context compared to conventional high throughput assays of homogenous 2D cell cultures. However, increasing the physiological complexity of cancer models makes them harder to image – limiting opportunities for high throughput (phenotypic) screening.

In a CRUK-funded Accelerator project, we aim to explore the trade-off between complexity of 3D cancer models and power of assays (in terms of single cell resolution and throughput) by developing and applying modular open source automated instrumentation optimised for 3D imaging of complex cell cultures with a range of optical properties. This automated 3D imaging instrumentation is intended to provide quantitative single cell-resolved readouts of drug-target engagement and responses in fixed and live cell cancer models. We will also explore cell culture and sample preparation (e.g. labelling, mounting, clearing) techniques to enable researchers to optimise 3D assays to address their specific cancer biology questions. Following instrument development at Imperial and the Crick, we will implement and apply these new capabilities, including with the University of Edinburgh, the ICR and the IRB Barcelona, to 3D cancer biology assays, e.g. to study heterogeneity in the response of cancer cells to chemotherapy – identifying which of the persisting cells are responsible for disease recurrence, to explore the role of the tumour microenvironment for quiescent resistant tumour cell sub-populations and to better understand side-effects of chemotherapy.

We are looking to train students in an interdisciplinary environment and applicants should have a first degree in bioscience or physical sciences with strong practical and computational skills. The PhD projects would drive projects exploring the novel technology to address the biological questions in the area described above. They will develop knowledge and experience in cancer biology, as well as experience of the chemistry associated with labelling proteins, cell biology techniques including culturing and assaying 3D cell cultures, and advanced optical microscopy and image data analysis.

One PhD project would be undertaken with co-supervision by Erik Sahai at the Francis Crick Institute and Chris Dunsby & Paul French in the Photonics Group at Imperial.

The second PhD project would be supervised by Iain McNeish in the Division of Cancer at Imperial, working closely with the Photonics Group.

Please contact Chris Dunsby, Paul French, Erik Sahai or Iain McNeish for further information.