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Cancer Stem Cells - Getting to the Root of the Problem (Professor Justin Stebbing)

Cancers are composed of actively proliferating cells which constitute the bulk of a tumour and a small population of cells, usually between 1-5% of the total cancer mass, called Cancer Stem Cells (CSCs). Recent advances in understanding suggest that CSCs are responsible for some of the most malignant features of cancer, including phenotypic and behavioural heterogeneity, dormancy and chemo-resistance as well as cancer dissemination. Metastatic dissemination (secondary cancer spread) and disease relapse are critical determinants of cancer prognosis. This process can take place many months or years after surgery to remove the primary tumour and/or chemotherapy, radiotherapy or other treatments have been delivered. It is as if the dandelion has been removed from the lawn, but the root is left below the surface to regrow at a later date.

CSCs have certain markers of identification, in the form of proteins on their surface. By applying specific capture techniques, we are now able to obtain the cells from within patients’ tumours and analyse their protein content. This allows for a much greater understanding of the pro-survival mechanisms that are operational within CSCs. Cancer genomics (the study of cancer genes and their structure, function and evolution) integrates multiple sequencing techniques and is rapidly illuminating the varying ways in which tumours form and metastasise in different patients. Nevertheless, a complete characterisation of the genomic and mutational variation of highly tumourgenic (tumour forming) and metastatic CSCs has not yet been undertaken.

Many studies on variability within tumours have looked at whole populations of cells and analysed the average levels of important genes, using DNA sequencing. This only gives a snapshot of the mechanisms taking place at the time of processing. Within a population of tumour cells, even adjacent cells can behave completely differently. Cellular 'switches' can be turned on or off, and the changes that cause these switches are often missed if only averages can be looked at. We are utilising a recently developed technology called 'single-cell sequencing' to better understand the variability within CSCs. Viewing a patient's tumour at single-cell resolution will, we hope, allow us to find rare cell types, and rare cell stages along cellular transitions: both of these phenomena can easily be missed when relying on average measurements of bulk cells. Indeed, the cancer stem cells responsible for many of a tumour's most malignant traits are usually a rare subset of total cells, making this technology uniquely equipped to investigate the characteristics of this cell type in the context of the whole tumour.

An early study using single-cell sequencing to examine glioblastoma, an aggressive brain tumour, even suggested that multiple subtypes of the disease may actually co-exist within a single tumour. We hope to obtain similarly important findings. Gaining such a comprehensive picture of how CSCs operate will help us answer hugely important questions such as: 'how could future treatments specifically target the most malignant cells?', 'why do certain patients not respond to treatments?' and 'what conditions allow some tumours to metastasise around the body?'.

The likely revelation of new drivers of cell state transition to and from the CSC population will permit the discovery of new molecular targets for the eradication of these cells. We are also looking to identify biomarkers, to help indicate which patients would be eligible for treatment.

This will be pioneering research which we hope will act as a catalyst for the design of targeted treatments to improve the survival prospects and quality of life for cancer sufferers worldwide.