Summary

Available Early Stage Researcher Positions:

In patients diagnosed with primary cancer, systemic therapy aims to eradicate clinically undetectable disseminated cancer cells that have already left the primary site. Interestingly, many driver mutations are found both in the primary cancer and relapsing lesions, suggesting that the genome of the primary tumour at the time of diagnosis may serve as a proxy for cells that ultimately give rise to relapses, whether via local, hematogenous, or lymphatic routes. We aim to generate high-resolution maps of the molecular networks that shape adaptation states, identifying the cancer cell states that facilitate initial survival of metastatic cells after dissemination and upon adjuvant therapy. We will employ a combination of experimental lineage tracing, CRISPR/Cas9 editing, single-cell sequencing (SC-seq), and extensive transcriptomic clinical datasets to comprehensively study metastatic cell fates.

Cancer progression involves two central capabilities: invading the stroma and adapting to hostile environments when colonising secondary organs. The vasculature plays a crucial role in tumour progression and therapy response, sharing signalling and metabolic pathways with cancer cells. Other stromal cells such as fibroblasts exhibit similar behaviour whereas the immune cell repertoire may support or limit progression owing to a complex integration of systemic and local cues. Our approach combines state-of-the-art experimental systems with clinical analyses to dissect the mechanisms of tumour-stroma interaction in metastasis. Extensive experimental evidence suggests that the tumour microenvironment and metastatic niches are potential targets for therapy. To this end, endothelial, fibroblast and immune cell driven engineered mouse models within this consortium represent unique opportunities.

Metastatic cancer typically becomes fatal within 5 to 10 years. Metastases often manifest asynchronously with the primary tumour, with timing influenced by factors like volume, stage, and molecular subtype of the primary tumour. For hormone-dependent tumours expressing oestrogen receptor or androgen receptor, recurrences may occur after extended asymptomatic periods. Understanding how disseminated tumour cells (DTCs) survive in low numbers after primary tumour resection and what determines their eventual expansion into clinically detectable metastases is crucial for addressing latency and treatment resistance. Similarly, understanding the clinical potential of CTCs and what adaptation steps they represent is central. We will employ SC-seq and in vivo models, epigenomics and transcriptomics, and isolation and characterization of CTCs to mechanistically study metastatic latency.

Beyond survival after initial arrival at the secondary site and during adjuvant therapy, metastatic cancer cells need to adapt to the new microenvironment before they can form clinically detectable metastases. These adaptive mechanisms can vary from patient to patient and between metastases across different metastatic sites within an individual. Identifying initial cellular populations, their interconversions, and potential plasticity can shed light on the molecular mechanism that facilitate the adaptive processes at the secondary site. This complexity, when analysed in drug-resistant metastatic disease, provides insight into phenotypic evolution, plasticity, therapy failure mechanisms, and potential therapeutic targets. We will use single cell transcriptomics and chromatin analysis, spatial proteomics, lineage tracing cassettes, CRISPR/Cas9 screens, and multiphoton in vivo confocal microscopy to gain a comprehensive understanding of metastasis expansion at distant organs.