Publication highlights

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.

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.

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.

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.

This paper demonstrates a cell intrinsic role for AHR in intestinal stem cells. AHR deficiency in intestinal epithelium causes dysregulation of the Wnt pathway, overproliferation of crypt stem cells and impaired epithelial differentiation following injury, culminating in tumorigenesis.

We investigated how intratumour heterogeneity affects response to checkpoint blockade and how cancers might be treated based on evolutionary principles. Durable clinical benefit to checkpoint blockade in lung cancer and melanoma was associated with a high burden of clonal neoantigens; in contrast, tumours that progressed early on therapy had a higher burden of heterogeneous neoantigens. We could predict clonal neoantigens present in every tumour cell and identify immune cells that recognise them, suggesting that development of adoptive T cell or vaccination strategies targeting such clonal neoantigens might limit therapeutic escape and resistance mechanisms.

A new study from the Swanton lab identified genetic changes in tumours which could be used to predict if immunotherapy drugs would be effective in individual patients.

Using new high-throughput imaging designed for rare cell subsets, we revealed that germinal centre B cells form uniquely patterned immune synapses to bind antigens. The separation of antigen into small clusters, along with specific cytoskeletal organisation results in enhanced mechanical forces transferred onto the B cell receptor-antigen bonds, increasing the mechanical affinity-discrimination power of germinal centre B cells compared to other B cell subsets. The work implicated germinal centre B cell mechanics in selection of high-affinity B cell clones in antibody responses and introduced novel DNA nanosensors for measuring cellular forces.

The MRTF-SRF and the YAP-TEAD transcriptional regulatory networks both respond to extracellular signals and mechanical stimuli: the MRTFs are controlled directly by G-actin, while YAP activity is somehow potentiated by F-actin. Cancer-associated fibroblasts play an important pro-invasive role in stimulating cancer progression, and previous studies have shown that this involves YAP-TEAD signalling. This paper shows that CAFs also exhibit mechanically-dependent MRTF activation, which is also required for their contractile and pro-invasive activity. The two pathways are mutually dependent, requiring recruitment of MRTF and YAP to DNA via their respective DNA-binding partners, and reflecting their ability to control cytoskeletal gene expression.

This is the first prospective study in any cancer type that resolved the origin of the metastasising clone in the primary tumour characterising its genetic features and uncovering high risk events that confer risk of death.

This is the largest genomic study ever to be conducted in renal cell cancer and the first to show how evolutionary features of the tumour impact the clinical phenotype. Patent arising.

In this study we identified the WNK1 kinase as a negative regulator of CD4+ T cell adhesion and a positive regulator of T cell migration. Furthermore, we showed that WNK1 controls migration through the OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter. This was an unexpected finding since WNK1 had been previously shown to regulate salt homeostasis in the kidney. Our study is the first to have implicated movement of Na+, K+ and Cl- ions in the regulation of T cell migration.

In this study we showed that the Dp1Tyb mouse model of DS has locomotor defects, mapped the causative genes to a 25-gene region and identified that Dyrk1a is one of these. Furthermore, we found an unexpected progressive loss of motor neurons in these mice and showed that a similar loss is seen in humans with DS.

Building on our successful biochemical reconstitution of topological cohesin loading onto DNA, we completed the reconstitution of both dynamic loading as well as unloading. We realised that both loading and unloading follow a very similar trajectory through sequential ATPase and kleisin gates, only one of which can be open at any one time. This formed the basis for our unified DNA passage proposal both into and out of the ring.

One of the major surprises of our iCLIP studies was the major role that transposable elements play as hubs for RNP assembly. Here, we uncover multiple roles of LINEs in RNP assembly, and show how this helps to create repressive environment in introns, while also driving the evolution of new tissue-specific exons.

Transcription factors typically activate transcription by recruiting cofactors, but our data in this paper illustrate a new function. We show that the sequence-specific transcription factor Rap1 prevents regulatory elements from initiating transcription in the divergent direction. We define a novel mechanism for providing directionality towards productive transcription, as Rap1 promotes directionality, at least in part, by directly interfering with transcription initiation in the divergent direction. Our study reveals a new important layer of regulation, describing how genomes restrict the accumulation of aberrant transcripts and ensure productive coding gene expression.

In this paper, we uncover the cell biological basis of a human ribosomopathy. Somewhat unusually, this project was spurred by a member of the public who asked us to create a Drosophila model of his son’s condition caused by a ribosomal mutation (RPS23[R67K]. Flies carrying this mutation are viable but display many markers of cellular stress. Surprisingly, this is not caused by insufficient protein synthesis capacity but instead by a reduced ability to eliminate misfolded proteins, perhaps because of an unusual burden from orphaned ribosomal proteins. We found that pharmacological or genetic inhibition of TOR significantly rescued cellular stress in these animals, suggesting a therapeutic strategy to alleviate the symptoms of this and other ribosomopathies.