Tracing the dynamics of epithelial cell competition in normal and perturbed states

The mechanisms that regulate cell fate promise fundamental insights into the pathways that promote tumour growth. Through advances in genetic lineage tracing and single-cell profiling, the functional identity, lineage relationships and fate behaviour of stem and progenitor cells have begun to resolve. Applied to epithelial tissues, these studies have challenged prevailing models, emphasizing the role of stochastic renewal programmes, fate priming and the flexibility of cell states during regeneration. Using a novel lineage tracing strategy based on variants of the multicolour Confetti reporter system, we will use quantitative modelling-based approaches to target the cellular and molecular mechanisms of epithelial cell fate, and how these programmes become subverted following the activation of oncogenic mutations. With a focus on columnar and squamous epithelia, where a foundational understanding of associated signalling pathways and transcriptional programmes is in place, we will define at clonal resolution the changes that take place in cell fate following the acquisition of oncogenic mutations, targeting tumour cells and the reaction of surrounding normal tissue – the tumour microenvironment. As prominent sites of disease, we will contrast tumour cell dynamics in the closed glandular arrangement of the intestinal epithelium and the open organization of the interfollicular skin epidermis and oesophagus.