Barrett’s oesophagus is a condition associated with gastric reflux that increases the chance of developing oesophageal cancer by 30-fold. A key question is how Barrett’s oesophagus arises from normal gastrointestinal tissue. However, because there are several different types of cells within Barrett’s oesophagus, research into the cellular origins of this tissue is difficult. To overcome this challenge, Ludwig Oxford’s Richard Owen, Michael White and David Severson from Xin Lu’s and Benjamin Schuster-Böckler’s labs performed single cell RNA sequencing on patient biopsies from Barrett’s and normal oesophagus. Their results, published in Nature Communications, show that a cell population in Barrett’s oesophagus had most similarity to normal oesophageal submucosal gland cells. This finding has implications for the clinical diagnosis of Barrett’s oesophagus.
The Cre-loxP system is a widely used experimental tool that allows selective and dynamic genetic manipulation. Cre recombinase is a protein that excises sections of DNA between two inserted DNA sequences called loxP sites. The production of the Cre protein can be controlled so that the targeted DNA, such as a gene, can be deleted at a specific time or in specific tissues. This powerful tool has enabled many insights into vascular biology. However, Ludwig Oxford’s Sophie Payne and Alice Neal from Sarah De Val’s group caution in a review article for Arteriosclerosis, Thrombosis and Vascular Biology that Cre mouse models need to be carefully selected and characterised before the resulting phenotypes can be analysed.
DNA, comprising a sequence of four bases (A, T, C and G), can be mutated in several different ways, for example C can mutate to A, or T to A etc. Different causes of mutation, such as UV light, result in distinct combinations of these mutations, called mutational signatures. Study of these mutational signatures allows scientists to learn more about the mechanisms that caused the mutations. In this article published in Genome Biology, Marketa Tomkova, Skirmantas Kriaucionis and Benjamin Schuster-Böckler explore how DNA replication timing and strand asymmetry affect mutational signatures, even those caused by chemical mutagens.
Three key signalling pathways in development (MAPK, PI3K and WNT) are frequently deregulated in cancer and respond to complex microenvironmental cues to regulate the activity of transcription factors. Some transcription factors act as master regulators to integrate signals from multiple pathways to control the expression of cell fate-determining genes. In this article published in PNAS, Kao Chin Ngeow and colleagues from Prof. Colin Goding’s lab characterise one such master regulator, MITF, a lineage survival oncogene with a central role in melanoma. In melanocytes, activation of GSK3 (downstream of the PI3K and WNT pathways) and BRAF/MAPK signalling results in dual phosphorylation of MITF. This exposes MITF’s nuclear export signal to cause relocation to the cytoplasm and subsequent decrease in MITF activity. This work has implications for the understanding of melanoma progression and the control of cell identity in development and disease.
A team of six researchers, including Ludwig Oxford’s Sarah De Val and those from Germany and USA, have been awarded a prestigious Fondation Leducq Transatlantic Networks of Excellence Programme grant. These collaborative awards provide $6 million over ﬁve years for work centred on cardiovascular and neurovascular disease. Sarah’s team will characterise the transcription factor Klf2 and its role in blood vessel biology.
Activation of the bacteria-sensing NOD receptors triggers inflammatory signalling via Receptor-interacting protein kinase 2 (RIPK2). Since RIPK2 inhibitors targeting the ATP-binding pocket have been shown to block this signalling pathway, it was assumed that RIPK2 kinase activity was important for signal transmission. In this work published recently in EMBO Journal, Hrdinka, Schlicher and colleagues from Mads Gyrd-Hansen’s lab demonstrate that kinase activity is in fact dispensable for NOD signalling and that these RIPK2 inhibitors are instead preventing the binding of the ubiquitin ligase, XIAP, and the subsequent XIAP-mediated ubiquitination of RIPK2 necessary for downstream signalling. This work could have therapeutic implications since NOD signalling is associated with several chronic inflammatory conditions such as Crohn’s disease.
It is important for cells to control the balance of nutrients – including glucose and amino acids – for proper cell function. A key regulator in this process is the transcription factor, TFEB, which travels to the nucleus upon nutrient limitation to activate the cell’s recycling of unwanted components to restore nutrient levels. Several mechanisms have been described for how nuclear import of TFEB is prevented when nutrient levels are high. In this article published in Nature Communications, Linxin Li, Hans Friedrichsen and colleagues from Prof. Colin Goding’s lab describe an additional control of TFEB cellular localisation. Both amino acid and glucose limitations can alter the phosphorylation status of TFEB in a way that inhibits its nuclear export and thus promotes the activation of cellular recycling. Because deregulation of nutrient levels occurs in many diseases including cancer and neurodegeneration, this work has implications for the development of potential therapeutic interventions.
The 7th Annual CRUK Oxford Centre Symposium was held on 15th June 2018 in the Mathematical Institute, Oxford. The day consisted of a varied programme of presentations, ranging from cancer epidemiology to cancer immunotherapy and ended with an inspiring talk from a patient who has benefited from Oxford’s research via an early phase clinical trial. In addition to the talks, the breadth of cancer research at Oxford was showcased by > 60 posters. ...
Ludwig Oxford’s Sarah De Val was selected to give the prestigious John French lecture at the British Cardiovascular Society Spring Meeting in Manchester. The lecture commemorates the work of John French, a vascular pathologist from the Dunn School of Pathology, Oxford, and is given by an early career scientist of exceptional promise. Sarah talked about her work on blood vessels in development and disease. (Image Copyright Jane Goodall 2018)