Dr Kevin Myant, Univeristy of Edinburgh & Dr Colin Steele, Cancer Research UK Scotland Institute
Research question
Cancer metastasis is the major clinical challenge for cancer management and accounts for the majority of cancer-related deaths. Cellular plasticity, the ability of cells to switch phenotypic states, is implicated as a major driver of metastasis. We have recently identified the chromatin-remodelling enzyme ATRX as an important mediator of cellular plasticity in colorectal cancer (CRC). Loss of Atrx promotes metastasis and leads to loss of colonic identity and emergence of mesenchymal and squamous-like cell states suggesting the acquisition of multi-lineage plasticity is a critical driver of metastasis (Cammareri et al., 2025). However, the mechanisms responsible for this process are poorly understood, limiting the development of therapeutic strategies to target it. The aim of this project is to determine the mechanisms that drive multi-lineage plasticity in metastasis and develop new ways of targeting it for therapeutic development.
Relevance to Cancer
Recent work from our lab and others has identified the emergence of mesenchymal and squamous-like cell states as a characteristic of late-stage, metastatic CRC (Cammareri et al., 2025 and Moorman et al., 2025). However, how these cell states emerge, and their functional importance to metastasis is not well understood. Our recent data has identified transcription factor (TF) networks with increased activity in these cell populations, some of which are associated with lineage specification. Based on this, we hypothesise that increased activity of lineage specifying transcription factors controls the emergence of highly aggressive cell states in CRC and targeting them will suppress metastasis. If correct, this will help us develop a better understanding of how cellular plasticity promotes metastasis and could lead to the development of novel therapeutic strategies to target this disease.
Techniques/model systems to be used
We will utilise 3D organoid models to define the contribution of different lineage specifying TFs to CRC metastasis. The organoid models used can be transplanted into recipient mice allowing both in vitro analyses of plasticity and in vivo determination of metastatic capacity. We will use inducible degron technologies (dTAG) to permit temporal depletion of the target proteins both in vitro and in vivo. Initially, we will investigate the function of the TFs Twist1 (mesenchymal) and Trp63 (squamous). Following TF depletion, alterations in tumour phenotype and rates of metastasis will be determined. As degron technology allows for temporal depletion, these models will allow us to determine the role mesenchymal and squamous-like plasticity at different stages of tumour progression and metastatic spread. We will further characterise the function of Twist1 and Trp63 using ATAC-seq, single-cell RNA-seq and phospho-proteomics following their depletion to identify the epigenetic changes that regulate cellular transition states during metastasis. Finally, we will construct organoid lines expressing genetically encoded fluorescent markers of mesenchymal and squamous-like cell states. This will enable us to screen candidate small molecules (identified from the characterisation experiments above) for those that impair the transition into these states. Together, this project will define the importance of multi-lineage plasticity in CRC metastasis and guide development of novel strategies to therapeutically target it.
Aims
1) Determine the function of Twist1 and Trp63 in mediating CRC metastasis
2) Explore how Twist1 and Trp63 depletion impact cellular plasticity
3) Screen candidate small molecules for inhibitors of cellular plasticity
For further information on the project or informal enquiries, please contact Dr Kevin Myant, This email address is being protected from spambots. You need JavaScript enabled to view it.
To place an application, please visit this site at the University of Edinburgh.
When submitting your application please make sure that you have also completed your application to the Windsor Fellowship and please upload the completed recruitment form.
Duration: 4 years, starting October 2026
Closing Date: 24th November 2025
Interview for this position will take place in January 2026
Lab Websites
Dr Kevin Myant - Colorectal Stem Cell Transformation
Dr Colin Steele - Advanced Colorectal Cancer
References
Cammareri, P., Raponi, M., Hong, Y. et al. Loss of colonic fidelity enables multilineage plasticity and metastasis. Nature 644, 547–556 (2025).
Moorman, A., Benitez, E.K., Cambulli, F. et al. Progressive plasticity during colorectal cancer metastasis. Nature 637, 947–954 (2025).