Publication highlights

This paper established that intestinal epithelial cells use BTNL/Btnl molecules to select for and regulate tissue-specific gamma delta T cell compartments. It established a biological mechanism by which epithelial cells communicate with local T cells at steady-state (“normality sensing”). Following on from our prototypic discovery of such a mechanism in mouse skin, the work established conservation of the process across tissues as well as across species. The system is unperturbed by microbial colonisation.

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.

This paper provides strong evidence that “atypical” B cells are short-lived activated B cells, and are probably the result of chronic stimulation and not the cause of chronic malaria. This questions the commonly held view that atypical B cells are evidence of an aberrant or defective response in malaria.

The priming signals in sterile chronic inflammatory diseases remained elusive. Moreover, NETs were mostly thought to serve as an antimicrobial defence mechanism. This work showed that NETs are proinflammatory and provide the priming signals for inflammation in atherosclerosis. It has important implications for our understanding of the mechanisms driving many inflammatory conditions and the important amplification mechanisms involving neutrophil-macrophage crosstalk.

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.

The paper was a broad collaboration with a team from one of our Partner Institutions and others, and illustrates how our learning from insights in the PKC field, here concerning kinase nucleotide pocket occupation, can impact our understanding of the broader kinome. Specifically the work demonstrates that the pseudokinase HER3 which is upregulated in cancer and drug resistance settings, undergoes essential nucleotide pocket occupation dependent changes in conformation to drive HER2 partner dependent signalling. Of importance clinically, the paper offers a route to small molecule-based intervention and also raises questions of inhibitor liability associated with HER3.

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.

We demonstrated aberrant intron retention in ALS-causing mutations. This is the first description of abnormal intron retention in ALS. The most significantly retained intron in is the SFPQ transcript, which 'drags' SFPQ protein out of the nucleus. SFPQ nuclear loss is a new universal molecular hallmark of ALS across iPSC, mouse models and in sporadic ALS post-mortem tissue.

In this paper we showed that cDC1 recruitment and infiltration in several mouse tumour models depends on the chemokines CCL5 and XCL1 produced by NK cells. In human cancers, CCL5/XCL chemokine transcripts correlate with gene signatures for NK cells and cDC1 and predict overall survival in melanoma, head and neck cancer, breast cancer and lung adenocarcinoma. Therefore, our data uncovered a mechanism for cDC1 recruitment into tumours that is translatable to humans and cancer patient survival.

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.

This study showed that epigenetic mechanisms play an important role in generating functional heterogeneity within tumours, and can override genetic alterations that initiate the disease by inhibiting cell proliferative potential during tumour growth. The finding that heterogeneous patterns of H1.0 are broadly observed in cancer and that H1.0 is an independent predictor of patient survival in multiple types of solid tumours makes a strong case for a general role of epigenetic regulators in cancer. Mechanistic characterisation of how H1.0 controls malignant self-renewing states also provided insights into general mechanisms through which the linker histone regulates gene expression.

Animals engage actively with their environment, yet how active sampling strategies impact neural activity was unknown. We showed that mice adapt sniffing during learning in a way that enhances neuronal representation. Furthermore, this work resolves a long-standing conundrum that seemingly non-olfactory information is prominently represented in the OB: context influences sniffing, which in turn changes neural activity.