Rethinking cancer therapies in the frame of cellular dormancy

Cellular plasticity, the ability to undergo molecular and physical changes, is a key adaptive mechanism that enables organisms to develop, regenerate and respond to stress. In cancer, however, it is one of the major underlying causes for resistance to therapy. This process allows cells to transition to distinct states and thereby gain the ability to evade immune responses, to accumulate new mutations which could enable resistance to antiproliferative drugs, colonise other organs or help metastatic tumour cells to adapt to new environments.

All of these can lead to tumour progression and/or recurrence. Plasticity manifests in many forms, but one of particular clinical relevance is cellular dormancy. Dormant cells enter a reversible cell cycle arrest named quiescence which enables them to resist to high levels of stress such as those encountered during tumour development or treatment, e.g. chemotherapy targeting cycling cells.

There is increasing evidence indicating that tumours contain subpopulations of slow-cycling or entirely quiescent cells which can evade therapy.

Dormancy results from a complex equilibrium between DNA damage and cell growth processes, involving master regulators like the p53 and Rb proteins, to enable the cells to cope with increasing genomic instability and levels of stress. These processes are crucial during early tumour development and manifest as a consequence of various mutagenic insults accumulated in the genome.

Yet, the specific mutational processes inducing cells into a dormant phenotype are completely unexplored. Moreover, the extent to which dormancy levels vary within a single tumour or between multiple affected individuals is unknown. Addressing these knowledge gaps could lead to a paradigm shift into cancer treatment management.

A cancer with particular relevance for the phenomenon of dormancy is oesophageal adenocarcinoma, an aggressive disease with consistently poor outcomes from both chemotherapy and immunotherapy and a 5-year survival rate of only 15%. We have shown that chemotherapy does not change the mutational make-up of this cancer significantly, suggesting that something beyond the genome must be driving resistance to this therapy.

Literature evidence and our own analyses indicate that dormancy could play a role. I propose to investigate the mechanisms leading to dormancy in this cancer and their potential therapeutic relevance. Beyond oesophageal cancer, various other tumour types show evidence of this phenomenon.

Brain tumours, particularly gliomas, show consistently high rates of dormancy which confers stem-like characteristics and resistance to standard therapeutic strategies. Sarcomas are highly metastatic, often due to latent micrometastases enabled by dormant cells. Understanding the emergence and clinical impact of dormancy in various cancer tissues could help rationalise tailored therapies for cancer patients.

Statistical methods such as matrix decomposition have recently enabled us to identify the distinctive genomic footprints of various mutagens (such as smoking or UV light) from DNA sequencing data. These inform us on how specific cancers developed and can be linked to gene expression programmes active in dormancy and their manifestation in the tissue.

In this regard, I will employ and develop cutting edge statistics, data integration and artificial intelligence methods on bulk, single cell and imaging datasets from oesophageal, brain and bone cancers to elucidate the genomic drivers, spatial heterogeneity and therapeutic relevance of dormancy in tumours.

The aim of this proposal is to provide an integrated view of how dormancy arises as a result of various mutational processes in cancer and how this impacts the broader cellular architecture of the tumour. I will employ this knowledge to redesign how cancer treatment is allocated by predicting the risk of resistance to therapies where dormancy may play a role.