Wiecek, Anna Julia; (2023) Evaluation of dormancy states in cancer and associated therapeutic opportunities. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tumour mass dormancy and cancer cell quiescence represent the two facets of cancer dormancy and play key roles in cancer development and progression. Quiescence describes the reversible, proliferative arrest of individual cancer cells that has been observed as a contributing factor of resistance to chemotherapy and other treatments targeting cycling cells. In contrast, tumour mass dormancy describes the state of no net tumour growth, which can arise due to inadequate tumour vascularisation or anti- tumour immune response, during which tumours can acquire additional mutations and establish a microenvironment permissive for growth. Currently, both dormancy states remain poorly characterised. This thesis presents computational frameworks for evaluating the two states and comprehensively profiles their abundance and associated genomic and cellular features across 31 solid cancers from the Cancer Genome Atlas. Using machine learning approaches, I demonstrate that cancer cell quiescence preferentially arises in less mutated tumours with intact TP53 and DNA damage repair pathways. I also highlight novel genomic dependencies, such as CEP89 amplification, which drive an impairment of quiescence. Similarly, mutations within CASP8 and HRAS oncogenes are shown to be enriched and positively selected in samples with tumour mass dormancy. I also highlight an association between APOBEC mutagenesis and both dormancy states. Moreover, tumour mass dormancy is shown to be associated with infiltration with macrophages and cytotoxic and regulatory T cells but a decreased infiltration with Th17 cells. Lastly, using single-cell data, I demonstrate that quiescence underlies resistance to a wide range of therapies, including treatments targeting cell cycle regulation, proliferative kinase signalling and epigenetic regulation. Ultimately, this analysis sheds light on the underlying biology of cancer dormancy states, potentially highlighting vulnerabilities that can be targeted in the clinic. It also provides a transcriptional signature of therapy-tolerant quiescent cells that could be explored further in the clinic to monitor patient therapy response.

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