Stem cell biology of the intestine

Cancers of the colon, like other cancers, arise from the abnormal growth of cells containing oncogenic mutations. This provides the motivation to understand in detail the molecular changes accompanying such mutations. In contrast the impact of mutations on cell fates within affected tissues receives relatively little attention. Yet cancers are comprised of expanded clones of cells. Every mutated clone has a natural history involving discrete steps that establishes the fate of the founding cell and of its clonal descendants to dictate their contribution to, and availability for, neoplastic transformation.

We investigate the origin of clones in the intestinal epithelium to understand the probability of their survival and expansion at each stage and how this varies with different mutations. By defining when during their natural history clones predisposed to cancer become permanently fixed and how much they subsequently grow we can tailor interventions appropriately: aiming either to promote their extinction or limit their growth.

Lineage tracing

To determine the fate of clones we need to be able to observe them. This can be done directly by visualizing them or indirectly using DNA sequencing to detect unique mutations. Visualisation can be done in a number of ways using genetically modified mice. It commonly involves inducing a low frequency of sporadic activation of reporter genes using tightly regulated site specific recombinases, e.g. Cre, Flp, Dre. The recombinases can be expressed from specific stem or progenitor populations, or throughout the tissue.  Spontaneous somatic mutations can sometimes be visualized directly.

The composition, frequency and size of clones are determined and this quantitative assessment lends itself to mathematical interpretations to describe the processes by which grow and become fixed and infer the behaviours of the original individually marked cells, that are commonly stem cells.

Stem cell extinctions and expansions characterize the process by which surviving clones can eventually become fixed in the epithelium – by occupying the individual glands or crypts that characterise the epithelium .

Stem cell and clonality

Renewing tissues are maintained by the production of cells by a small populations of founder stem cells. It follows that of the cells undergoing mutation it is the stem cells are the most likely to give rise to clones that become fixed. Moreover, pre-cancerous lesions may still be maintained by stem like cells. For these reasons we are interested in the properties of stem cells and how they are programmed and regulated to allow self-renewal.

However, stem cells are not an entirely stable population. Plasticity whereby cells can change their properties or identity in unexpected ways is increasingly recognized both in damaged tissues and in the steady state.