Bailey, Sasha; (2025) Determining the cell intrinsic and microenvironmental contributions to subclone dynamics in cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Intratumour heterogeneity (ITH) is a consequence of tumour evolution and impedes effective cancer treatment. The interplay between evolving tumour subclones, the physical tissue context and non-cancerous cells of the microenvironment underlies this heterogeneity and the associated therapeutic failure. Understanding the contributions of these determinants to tumour evolution is instrumental for improving strategies to target cancer therapeutically. Here, subclonal multicolour lineage tracing was used to interrogate cell intrinsic and microenvironmental contributions to patterns of subclone expansion during tumorigenesis. This approach enabled experimental dissection of factors that define subclone fate in vitro and in vivo. First, spatial and temporal subclone dynamics were assessed in equivalent populations, where there are no intrinsic fitness differentials between cells, then in non-neutral populations, where a subpopulation of cells has an intrinsic fitness advantage. In homogeneous cancer cell populations, the data suggested that a density-induced spatial restriction of proliferation leads to unequal subclone fates despite population equivalence. This proliferative arrest was universal but at cell type specific thresholds that related to intrinsic differences in cellular motility. Furthermore, perturbation of cell migration delayed the induction of proliferative arrest and equalised subclone fates by granting spatial independence from cell ‘place of birth’. Here, motility was tuned by exogenous drug treatments, coculture with cancer associated fibroblasts or by growth in different extracellular matrices. Irrespective of how cell migration was tuned, subclones fragmented and subclone fate became less dependent on location. As physical restrictions on proliferation were a critical determinant of subclone fate, the impact of altered mechanosensation was interrogated using constitutively active YAP. Here, YAP5SA subclones only dominated over control cells under spatial confinement, revealing the importance of spatial context in defining subclone fitness. Finally, the impact of spatial constraints on therapy resistant subclone expansion were characterised. This revealed that tuning migration modulated the dynamics of resistant subclone dominance due to spatial restrictions on growth influencing the ability to ‘realise’ any intrinsic competitive advantage. Overall, the results signify the importance of spatial context in defining subclone fate in conjunction with cell intrinsic fitness.

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