Publication highlights

Stem cell numbers in the hippocampus of young adults stabilise due to coordinated changes in stem cell behaviour which ensures lifelong hippocampal neurogenesis, according to new research from the Guillemot lab.

This paper shows how temporal information in the zebrafish embryo is transformed into a spatial pattern. We demonstrate how the Nodal signalling gradient is formed in the early zebrafish embryo and show that its size and shape are determined by a temporal signal activation window created by a microRNA-mediated delay in the translation of Lefty, a Nodal antagonist. This paper was important as it not only challenged the long-held view in the field that the Nodal gradient was formed by a reaction–diffusion mechanism, but highlighted the importance of signalling duration in gradient formation.

Using a combination of structural biology, genome editing, and biochemistry, a new study from the Hill lab showed that Shprintzen–Goldberg syndrome is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, as previously predicted.

How inflammatory programmes are tuned to recruit sufficient numbers of neutrophils to clear microbes of different size remained unknown. Furthermore, neutrophils were not thought to serve as major regulators of inflammation in vivo. We showed that reactive oxygen species localisation allows neutrophils to regulate their own recruitment by setting the appropriate level of cytokine production.

We addressed the hypothesis that impairment of neuroprotective astrocytic mechanisms are disrupted in ALS using in vivo models, and patient-specific iPSCs. We found that EphB1, a neuronal signal, can induce a neuroprotective astrocyte phenotype through the EphrinB1 receptor / JAK-STAT pathway and that this response fails in ALS astrocytes.

A study led by Rickie Patani has identified the trigger of a key cellular change in amyotrophic lateral sclerosis (ALS), a type of motor neurone disease. The findings could help develop new treatments for many neurological diseases with the same change, including Parkinson’s and Alzheimer’s.

Immune cells such as type 1 conventional dendritic cells (cDC1) can “eat” (phagocytose) dead tumour or virally-infected cells and present associated antigens to CD8+ T cells to elicit a tumour- or virus-specific cytotoxic T cell response. How antigens from the debris get presented on MHC class I (MHC-I) molecules on cDC1 has long been puzzling as MHC-I normally presents antigens found in the cytosol. This paper shows that cDC1 use the DNGR-1 receptor to induce phagosomal rupture, releasing the debris-associated antigens into the cytosol. These findings have implications for our understanding and manipulation of immunity to infection and cancer.

In this paper, we uncovered a potent mechanism of cancer immune evasion, namely cyclooxygenase (COX)-dependent secretion of prostaglandin E2 (PGE2) by tumour cells. We further showed that the growth of PGE2-secreting tumours in mice can be reversed by a combination of checkpoint blockade immunotherapy and COX inhibitors, suggesting that COX inhibition might be a useful addition to both conventional and immune-based therapy of cancer. This paper led to seven clinical trials worldwide to test combinations of prostaglandin E2 inhibition with checkpoint blockade cancer therapies.

Our previous work showed how stromal fibroblasts lead the collective invasion of cancer cells, and documented how remodelling of the extracellular matrix was important for this behaviour. Following our observation of direct cell-cell contacts between cancer cells and fibroblasts, we hypothesised that the two cells might be mechanically coupled; therefore, we began collaborating with Xavi Trepat (IBEC Barcelona), who is a world leader in the mechanics of multi-cellular systems. By biophysical measurements and a range of conventional cell and molecular biology manipulations, we demonstrated that fibroblasts actively ‘pull’ cancer cells into the surrounding extracellular matrix.

Research from the Scaffidi lab has developed a new strategy to identify cancer-specific vulnerabilities. They identified a group of proteins, called the male-specific lethal (MSL) acetyltransferase complex, which could be used to increase chromosomal instability in cancer cells without inducing severe adverse effects in normal tissues.

This paper established the AHR induced feedback system of cytochrome P4501 metabolising enzymes as critical regulators of AHR signalling. Excessive ligand degradation via Cytochrome P4501 phenocopies AHR deficiency and has detrimental consequences for intestinal health which can be counterbalanced by increasing the intake of AHR ligands in the diet. The intestinal epithelium acts as gatekeeper for the supply of ligands throughout the body emphasising the importance of the gut barrier for whole body physiology.

A detailed, genome-wide study of the transcriptional response to DNA damage, including the identification of genes that start expressing short, alternative splice isoforms after genomic insult. One of these genes, ASCC3, normally expresses a protein-coding mRNA, but after UV-irradiation shifts expression to a short non-coding RNA isoform, which is important for survival after DNA damage. The protein-coding ASCC3 isoform counteracts the function of the non-coding isoform, indicating crosstalk between them.

This TRACERx work shows that bespoke patient-specific panels to analyse ctDNA can be used to monitor MRD recurrence and tumour branched evolution in the adjuvant setting in the absence of macroscopic disease, and that tumour Ki67 index, necrosis, squamous histology and FDG-PET avidity are closely associated with ctDNA release. We further demonstrate the limitations of ctDNA approaches for early detection as a function of tumour volume and cancer cell number, and show that the subclone identified in ctDNA prior to disease recurrence is identical to the tumour subclone identified at metastatic sites, permitting adjuvant MRD studies to prevent recurrence.