Publication highlights

This paper solves the Wnt solubility problem, which has preoccupied the Wnt field for the past 15 years. It explains how the lipid of Wnts can be maintained in the extracellular space.

By merging the power of molecular genetics, basic physical chemistry and mathematical modeling we show quantitatively how an inert protein, GFP, can be turned into a morphogen that provides positional information in a developing tissue, the Drosophila wing disc. This is the first time that an active synthetic morphogen gradient has been reconstituted in vivo. Because the properties of the synthetic gradient can be experimentally modulated, a physical analysis of molecular determinants of morphogen gradients becomes possible.

In this paper we show that the ability of cells to survive glutamine depletion depends on aspartate metabolism, which is supported by the aspartate/glutamate transporter SLC1A3. The tumor suppressor p53 is shown to induce the expression of SLC1A3, explaining in part how p53 can help cancer cells survive under glutamine starvation.

We show that the clustering of cancer cells following detachment from ECM results in hypoxia, which activates mitophagy to remove damaged mitochondria and reductive metabolism to support glycolysis. These responses limit mitochondrial ROS production, allowing cell survival and metastasis.

Targeting the nutritional requirements of cancers through selective dietary intervention is an emerging therapeutic approach. Dietary limitation of the non-essential amino acids serine and glycine can limit the growth of some, but not all, cancers. This study extends this approach by showing combined treatment with an inhibitor of the intrinsic serine synthesis pathway with a serine/glycine free diet improves the therapeutic response and inhibits the growth of cancers that are not responsive to the diet alone. Extension of this work to human studies may offer an important new avenue for the treatment of a broad range of cancers.

We showed that interferons (IFNs), known to have antiviral effect, can aggravate respiratory viral infection if present late during infection when epithelial repair sets in. IFN-β and, most potently, IFN-λ reduce airway epithelial proliferation and differentiation in that recovery phase. This is important to understand the complex roles of IFNs in viral infections and has important implications for IFN treatments as presently discussed for COVID-19.

The Arp2/3 complex, consisting of seven evolutionarily conserved subunits, generates branched actin networks during many fundamental cellular processes. Taking advantage of actin based motility of Vaccinia virus as a model system, we demonstrate for the first time that in humans the Arp2/3 complex is actually a family of different complexes with distinct actin-nucleating properties.

The generation of CRISPR-Cas9 GEN1 k/o cell lines (supplemented with MUS81 siRNA) allowed us to develop the first model system to analyse the phenotypes of ‘resolvase-deficient’ human cells. We discovered that recombination intermediates persist until anaphase (despite the presence of the BLM-TopoIII-RMI1-RMI2 dissolvasome) where they form ultra-fine bridges (UFBs). These UFBs represent a new class of ultrafine bridges (we termed them HR-UFBs) distinct from replication stress induced UFBs or centromeric UFBs. HR-UFBs were targeted and processed by PICH/BLM, leading to the formation of ssDNA bridges that were broken at cytokinesis. Loss of GEN1 and MUS81 activity led to synthetic lethality.

First description of the SMX tri-nuclease that resolves recombination intermediates. Composed of SLX1-SLX4, MUS81-EME1 and XPF-ERCC1, the six-subunit complex was purified following baculovirus expression in insect cells. Characterization of the Holliday junction cleavage reaction revealed that the first incision was introduced by SLX1-SLX4, while the second was mediated by MUS81-EME1. We also found that MUS81-EME1 was activated by interaction with the SLX4 scaffold, ensuring that the second cut occurs in concert with SLX1-SLX4’s initial incision. The formation of SMX and activation of MUS81-EME1 provides a mechanistic basis for restriction of SMX activity to the later stages of the cell cycle.

A study led by the West lab has found that blocking a specific protein could increase tumour sensitivity to treatment with PARP inhibitors. Their work suggests that combining treatments could lead to improved therapy for cancer patients.

This work used high-resolution PET/CT imaging to establish for the first time in humans the existence of a high-risk asymptomatic transition state between latent infection and active disease. The technique is thus a phenotypic benchmark for further experimental medicine studies of interventions to prevent progression of asymptomatic subclinical tuberculosis.

Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. This is the first vaccine against tuberculosis to be shown effective in humans since the advent of BCG in 1921. A product development and further testing plan has recently been agreed and we will contribute to the latter.