Lucas, Olivia; (2025) Characterising the evolutionary dynamics of cancer proliferation and altered replication timing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cancer is an evolutionary process, resulting in heterogeneous tumours composed of genetically distinct clones with different phenotypes. While proliferation is a key cancer phenotype associated with prognosis, it is unknown whether it differs between clones within the same tumour. However, this may be important, as clone proliferation may link to aggressive clone behaviours such as metastasis. In four main parts, this thesis explores proliferation heterogeneity and its impact on tumour progression, as well as potential genetic and non-genetic mechanisms underlying such phenotypic differences. First, I introduce and validate SPRINTER, a novel algorithm that uses single-cell whole-genome DNA sequencing data to enable the accurate identification and clone assignment of replicating cells, providing a proxy for clone-specific proliferation. Second, I apply SPRINTER to a newly-generated, longitudinal, primary-metastasis matched dataset of 14,994 non-small cell lung cancer cells, revealing widespread clone proliferation heterogeneity, supported by orthogonal analyses including Ki-67 pathology, nuclei microscopy, and clinical imaging. Third, I demonstrate that highly proliferative clones have increased metastatic potential and circulating tumour DNA shedding. Moreover, leveraging previous breast and ovarian cancer datasets, I reveal that high proliferation clones have increased rates of genomic variants, which may confer an evolutionary advantage, and are enriched for proliferation-related gene amplifications, potentially underlying this phenotype. Lastly, I investigate whether altered replication timing (ART), an important type of non-genomic alteration, may drive clone phenotypes and cancer progression. I demonstrate that ART is present and linked to genomic alteration patterns and gene expression in patient tumours. Furthermore, I reveal clone-specific ART and concurrent expression changes in proliferation- and metastasis-related genes unique to metastatic, proliferative clones. This thesis thus explores two key aspects of dysregulated cell cycling, namely proliferation and ART, and simultaneously maps genetic, phenotypic and epigenetic features to cancer evolution, providing a framework for the future identification of clones with aggressive phenotypes.

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