A single tumour can harbour a mix of cells that respond differently to the same drug, and this hidden diversity is why many cancers relapse. The problem is that standard biopsies sample only a tiny fraction of the tumour, missing the resistant cells that later drive disease progression. Repeated biopsies are often too risky or painful for patients. This project will instead capture and analyse Circulating Tumour Cells (CTCs)—cancer cells that have broken off into the bloodstream. Because a blood draw is far simpler than a tissue biopsy, CTCs offer a way to track a tumour’s changing genetic makeup over time without invasive procedures. The team will establish a dedicated facility at UCL to perform single-cell genetic sequencing on these rare cells, first refining the protocols and then testing them in patients undergoing cancer treatment. If successful, this approach could give clinicians a real-time window into which therapies are working and why others are failing. It would also allow researchers to study how CTCs survive in the bloodstream and form metastases—the cause of 90% of cancer deaths—potentially revealing new targets for drugs that block the spread of the disease.
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One of the major challenges in the treatment of cancer is the ability to predict which patients will respond to which therapy and to understand why patients stop responding. We know that cancer arises from a single cell that has undergone reprogramming so that its growth becomes deregulated. During subsequent growth, the tumour becomes increasingly heterogeneous such that the response to therapy and ability to metastasise may vary. A consequence of this this heterogeneity is that a proportion of the tumour may be sensitive to therapy while the remainder is resistant. Hence, therapy selects our resistant cells that ultimately result in relapse or progression of disease. The only way to understand tumour heterogeneity is to sample the tumour tissue by taking biopsies, but even this may be misleading since only a proportion of the tumour is surveyed and important variability may be missed. Additionally, it may be difficult, dangerous or unacceptable to patients to perform multiple biopsies at various time points throughout the patient journey. A possible solution to this is to study Circulating Tumour Cells (CTCs) as surrogates of tumour tissue. CTCs are cells that are shed into the circulation and can be isolated from the blood for further analysis. CTCs are very rare cells by comparison with blood cells and highly sophisticated technology has been developed to enrich for CTCs and isolate them. In parallel there have been technological advances in genetic sequencing such that we can now identify mutations and analyse gene expression in single cells. This means that, for the first time we can begin to understand tumour heterogeneity at the single cell level. Our proposal seeks to establish a dedicated facility with state of the art equipment to enable scientists at UCL to study CTCs and improve the outcomes for patients with cancer. Initially we will establish protocols to undertake complex single cell analysis and then develop and validate tests in patients who are undergoing treatment for cancer. We will also study these cells in order to understand how they are able to successfully spread through the blood stream to other organs and cause metastases. Metastasis is responsible for the death of 90% patients with cancer and it is critical to understand how this happens in order to develop more effective therapies.
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