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Normal homeostasis of adult intestinal epithelium and repair following tissue damage is maintained by a balance of stem and differentiated cells, many of which are still only poorly characterised. Enteroendocrine cells of the gut are a small population of differentiated, secretory cells that are critical for integrating nutrient sensing with metabolic responses, dispersed amongst other epithelial cells. Recent evidence suggests that sub-sets of secretory enteroendocrine cells can act as reserve stem cells. Given the link between cells with stem-like properties and cancer, it is important that we identify factors that might provide a bridge between the two. Here, we identify a sub-set of chromogranin A-positive enteroendocrine cells that are positive for the developmental and cancer-associated transcription factor Brachyury in normal human small intestinal and colonic crypts. Whilst chromogranin A-positive enteroendocrine cells are also Brachyury-positive in colorectal tumours, expression of Brachyury becomes more diffuse in these samples, suggesting a more widespread function in cancer. The finding of the developmental transcription factor Brachyury in normal adult human intestinal crypts may extend the functional complexity of enteroendocrine cells and serves as a platform for assessment of the molecular processes of intestinal homeostasis that underpins our understanding of human health, cancer and aging., The authors would like to thank the following organisations for supporting this work: J. Jezkova, R.J. McFarlane & J.A. Wakeman are supported by Cancer Research Wales; J.S. Williams is supported by Coleg Cymraeg Cenedlaethol; J. Sammut and R.J. McFarlane are supported by NWCR (grant no. CR950); S. Gollins is supported by National Institute for Social Care and Health Research Academic Health Science Collaboration (NISCHR AHSC) Clinical Research Fellow. F.Pinto is supported by Fundação para a Ciência e Tecnologia (FCT; grant no. SFRH/BD/81369/2011). R.M. Reis is recipient of a Brazilian National Counsel of Technological and Scientific Development (CNPq) scholarship. Geraint Williams is supported by the Wales Gene Park. are supported by NWCR (grant no. CR950); S. Gollins is supported by National Institute for Social Care and Health Research Academic Health Science Collaboration (NISCHR AHSC) Clinical Research Fellow. F.Pinto is supported by Fundação para a Ciência e Tecnologia (FCT; grant no. SFRH/BD/81369/2011). R.M. Reis is recipient of a Brazilian National Counsel of Technological and Scientific Development (CNPq) scholarship. Geraint Williams is supported by the Wales Gene Park., info:eu-repo/semantics/publishedVersion

The T-box transcription factor Brachyury is expressed in a number of tumour types and has been demonstrated to have cancer inducing properties. To date, it has been linked to cancer associated induction of epithelial to mesenchymal transition, tumour metastasis and expression of markers for cancer stem-like cells. Taken together, these findings indicate that Brachyury plays an important role in the progression of cancer, although the mechanism through which it functions is poorly understood. Here we show that Brachyury regulates the potential of Brachyury-positive colorectal cancer cells to proliferate and reduced levels of Brachyury result in inhibition of proliferation, with features consistent with the cells entering a quiescent-like state. This inhibition of proliferation is dependent upon p27Kip1 demonstrating that Brachyury acts to modulate cellular proliferative fate in colorectal cancer cells in a p27Kip1-dependent manner. Analysis of patient derived colorectal tumours reveals a heterogeneous localisation of Brachyury (in the nucleolus, nucleus and cytoplasm) indicating the potential complexity of the regulatory role of Brachyury in solid colorectal tumours.