Deciphering the Role of Chromosomal Instability and Tumour Microenvironment in Cancer Evolution
Primary Supervisor: Dr Wei-Ting Lu
Second Supervisor: Professor Eileen Parkes
Project Overview
The Chromosomal Instability lab is interested in the mechanisms by which cancers karyotype mutates and evolves to become resistant to therapy. By understanding the underlying mechanism driving cancer evolution, we aim to overcome therapy resistance and identify novel therapeutic opportunities. Recently, we have identified that FAT1 alterations, which frequently occur in lung and oesophageal cancers, can lead to whole-genome doubling (WGD) through the dysregulation of the Hippo signalling, and elevated chromosomal instability (CIN) through an elevated rate of micronuclei formation (Lu et al., Nature Cell Biology 2025). WGD creates a tetraploid genome, which can buffer the effects of deleterious mutations and provide a platform for further chromosomal alterations. It has been shown that the combination of WGD and CIN can lead to dismal clinical outcomes. Beyond intrinsic genetic changes, CIN also influence how cancer cells interact with microenvironment. Through the activation of autocrine signalling, such as IL-6, cancer cells with high CIN can interact with the tumour environment and create a chemo-resistant niche (Gilbert and Hemann, Cell 2010; Hong et al., Nature 2022). Furthermore, this might also increase the possibility of horizontal transfer of genetic material among cancer cells (Xu et al., Cell Discovery 2022). Both phenomena are key contributors to drug resistance in cancer therapy. To visualise the interplay between CIN and microenvironmental changes, this project will generate oesophageal and lung cancer cell line co-culture systems expressing neonGreen-H2B and mCherry-H2B, respectively. Micronuclei formation and transfer rate, cGAS-STING activation rate will be monitored in co-culture experiments using microscopy. The contribution of the tumour microenvironment towards drug resistance rate, particularly the resistance against targeted therapy, will be investigated. The project will improve our knowledge of how microenvironment factors can contribute to cancer evolution trajectory, with the long-term aim to reveal new avenues to overcome drug resistance in highly genomic unstable cancers.
Training Opportunities
This project will provide training for molecular and cell biology techniques, including cell culture, transfection, stable cell line generation, fixed and live-cell fluorescence microscopy, flow cytometry, quantitative RT-PCR, image analysis and western blotting. The successful applicant will develop strong experimental and analytical skills, with the ability to formulate scientific hypotheses, problem-solve and develop novel methodologies. By working within a dynamic and interdisciplinary environment, the applicant will gain essential experience in collaborative research across medical and basic sciences, while enhancing their ability to efficiently communicate and present their data both in writing and orally. They will be able to critically read and analyse scientific literature, fostering a deep understanding across various aspects of cancer biology. This training will prepare them for further academic research or roles in translational and biomedical science.
References
Lu, W.T., Zalmas, L.P., Bailey, C., Black, J.R., Martinez-Ruiz, C., Pich, O., Gimeno-Valiente, F., Usaite, I., Magness, A., Thol, K. and Webber, T.A., 2025. TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling. Nature Cell Biology, 27(1), pp.154-168.