Deciphering the molecular determinants of pre-malignant mesothelial cell fitness to identify opportunities for cancer interception in pleural mesothelioma

Primary supervisor: Sam Janes, UCL

Secondary supervisor: Stuart McDonald, Queen Mary University of London

Project

Pleural mesothelioma (PM) is an incurable cancer of the lining of the lung (pleura) arising from asbestos-induced injury of the mesothelial cell monolayer [1]. The latency period of ~30-40 years between asbestos exposure and diagnosis presents a window of opportunity for intercepting premalignant disease and preventing cancer in high-risk patients. To achieve this, we must first delineate the processes that underpin transformation of mesothelial cells, identifying opportunities to intercept pre-malignant disease.

We hypothesise that chronic asbestos-induced injury creates a mosaic of mesothelial cell clones harbouring tumour suppressor alterations across the pleura – a cancerised field. Competitive selection of these clones drives the earliest stages of mesothelioma development. We propose that alterations of tumour suppressor genes which are frequently mutated in mesothelioma (BAP1, CDKN2A/B, TP53, NF2) [2] confer a fitness advantage enabling dominant clones to tolerate the oxidative, inflammatory microenvironment induced by asbestos-injury and outcompete their neighbours. We aim to identify which alteration(s) contribute to clonal dominance of mesothelial cells and give rise to the earliest mesothelioma lesions. We will then identify molecular dependencies of these clones for interception of cancer formation.

We will use CRISPR-Cas9/RNA-interference approaches to perturb combinations of tumour suppressor genes in fluorescently labelled untransformed mesothelial cells. We will quantify their competitive dynamics in long-term self-sustaining cultures using flow cytometry and live-cell imaging to determine which alterations result in clonal dominance. We will assess how these alterations enable mesothelial cells to persist and tolerate oxidative, inflammatory environments modelling the asbestos-injured pleura. Through transcriptomic profiling of dominant and non-dominant clones we will identify pathways that underpin competitive fitness. We will validate the functional contribution of these pathways to clonal dominance and use genetic and pharmacological inhibition to determine whether pre-malignant clonal expansion can be prevented. We will evaluate the most promising interception strategies in existing genetically engineered mouse models developed by our long-standing collaborators.

The PhD student will benefit from a collaborative supervisory team comprising Prof Sam Janes, a leader in respiratory and pleural medicine, mesothelioma cell biology, and cancer early detection and Prof Stuart McDonald, an expert in field cancerisation, pre-malignant clonal dynamics of epithelia, and identifying the earliest stages of cancer development [3-5].

Candidate background

This project would suit a candidate with a background and interest in epithelial cancer cell biology and is primarily a wet-lab project, with some elements of complementary bioinformatic analysis. Prior experience of microscopy, cytometry, cell culture, molecular biology, and cell competition would be beneficial. The student will benefit from being embedded in two internationally recognised institutes combining expertise in mesothelioma cell biology and modelling expansion of dominant pre-malignant epithelial clones. They will receive interdisciplinary training within UCL and Barts Cancer Institute in techniques including advanced live-cell microscopy, CRISPR engineering, flow-cytometry, cell competition assays, quantification of clonal dynamics, transcriptomic analyses and computational biology. The student will be expected to work independently and be self-motivated but will benefit from direct day-to-day supervision from an experienced postdoctoral fellow. They will also benefit from additional pre-existing collaborations with several world-leading experts in mesothelioma and pleural disease.

Potential placements

1. Stuart McDonald, Barts Cancer Institute, Queen Mary University of London
2. James Reading, Cancer Institute, UCL
3. Nicholas McGranahan, Cancer Institute, UCL

References

1. Janes S.M., Alrifai D., Fennell D., NEJM, (2021)
2. Bueno R., Stawiski E.W., Goldsstein L.D., et al., Nature Genetics, (2016)
3. Kolluri K.K., Alifrangis C., Kumar N., et al., eLife, (2018)
4. Evans J.A., Carlotti E., Lin ML. et al, Gastroenterology, (2022)
5. Lin ML et al., Biorxiv (2025). https://doi.org/10.1101/2025.06.09.657642