Publication highlights

An important aspect of cancer research is the model systems that researchers use to test new therapies. Within the TRACERx lung cancer study, researchers from the CRUK Lung Cancer Centre of Excellence have performed a direct comparison of patient tumours and a commonly used laboratory model - ‘patient-derived xenograft’ or ‘PDX’ models - in which patient tumour tissue isgrown within immunocompromised mice.

The researchers found that patient tumours are often genetically complex, with many co-existing subclones (groups of cell populations with different characteristics). However, the PDX models often only represented one of these subclones. This over-simplicity of PDX models might limit their ability to predict patient responses. These findings will shape the future use of PDX models in lung cancer research and clinical studies.

Research from the Crick has highlighted the importance of matching donor and recipient sex when transplanting haematopoietic stem cells from humans into mice for research. The researchers assessed engraftment of leukaemia stem cells from 38 patients with AML and umbilical cord blood stem cells from healthy donors. Initially, it looked like leukaemia cells from male patients engrafted better than female patients, but this effect disappeared once the patient and recipient mouse were the same sex. he female AML cells were much more sensitive to recipient sex than male AML cells, as engraftment proved very challenging when using male mice. In general, male AML cells engrafted better in both male and female mice.

The ring-shaped MCM helicase enzyme is loaded around double-stranded DNA as a structure called a 'double hexamer' which is inactive before DNA is replicated. Upon activation, two split MCM single hexamers transition to encircling single-stranded DNA, establishing divergent replication forks. Researchers at the Crick investigated how this happens, by visualising helicase activation under the electron microscope. They found that Mcm10, the factor promoting initiation, wedges itself in between two MCM rings so that the double hexamer is broken in two. Mcm10 also constricts the MCM ring pore, forcing one of the two DNA strands to escape. These mechanisms ensure that chromosomes are replicated only once per cell cycle, preventing chromosome instability and cancer.

Researchers at the Crick have developed a new method using single-cell techniques and AI to map how gene expression changes over time during cell fate decisions. They developed a metabolic labelling system called sci-FATE2 to generate high-quality data about the dynamics of gene activity in a single cell over time. They also developed new generative AI models to analyse the dataset. These methods were used to study the development of the mouse neural tube, by studying the differentiation of 45,000 embryonic stem cells. They found that this process occurs as two distinct fate decision points and were able to identify cells at the decision points and the genes involved in decision making. This new system could help to target and manipulate specific developmental events, which would contribute to the use of stem cells for disease modelling and regenerative medicine.

Researchers at the Crick investigated cGAS-STING, a pathway that evolved to sense cytoplasmic DNA following bacterial or viral infection, triggering an immune response. They used ionising radiation or genotoxic compounds to damage nuclear DNA, which then formed micronuclei - small compartments that encapsulate the damaged DNA in the cytoplasm. The researchers found that micronuclei induced by radiation failed to activate cGAS-STING signalling, as did genotoxic compounds such as reversine and hydroxyurea. This was due to the presence of histones in the micronuclei that package DNA into chromatin, which inhibits activation of the cGAS-STING pathway. This research challenges the notion that all cytosolic DNA in micronuclei activates cGAS-STING and suggests potential limitations for using genotoxic drugs to stimulate the immune system in cancer therapy.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease, estimated to be the third biggest killer worldwide (WHO). Researchers at the Crick investigated a gene associated with COPD risk called FAM13A. They found that FAM13A exists in short and long forms in humans and that only the longer form can act as an enzyme in specialised ‘multiciliated’ cells in the airway. These cells contain projections called cilia whose coordinated beating moves mucus out of the lungs. By genetically removing the long form of FAM13A in human cell cultures that resemble the air-exposed lining of airways, the team showed that FAM13A is necessary for coordinating cilia movement. In an additional experimental model for multiciliated cells, they reduced Fam13a expression in Xenopus (frog) embryos, which also led to defects in cilia activity. This research could inform why mutations in the FAM13A gene are linked to COPD in humans.

The human RAD52 protein plays an important role in several cellular processes, including the repair of chromosome breaks and the maintenance of telomere length (structures at the end of chromosomes) to avoid cellular aging. During DNA repair, it provides an alternative to the BRCA2 protein, which is mutated in many inheritable breast, ovarian and prostate cancers. Consequently, targeting RAD52 could be used to kill tumours with BRCA2 mutations, where growth is uncontrolled. To elucidate the mechanism of repair by RAD52, we determined the atomic structure of the protein using cryo-electron microscopy, and found that the protein forms a ring in which the broken DNA wraps around the outside of the ring. Having the atomic structure gives us new insights into ways to identify small molecules that can be used to inhibit repair by RAD52 and kill BRCA2-defective tumours.

Researchers from the University of Cape Town and the Crick worked together to investigate vitamin D supplementation and growth in children. Results from a clinical trial, conducted in a large number of African schoolchildren in Cape Town, South Africa, showed that a 3-year course of weekly vitamin D supplementation was effective in elevating vitamin D levels, however this was not associated with any effect on growth, body composition, pubertal development or lung volumes. There has been a lot of interest in the links between vitamin D deficiency in childhood and slower linear growth, reduced lean mass, obesity and precocious puberty, but this study suggests that vitamin D supplementation wouldn't be a useful intervention.