Publication highlights

Human induced pluripotent stem cells (iPSCs) mimic early embryos and can become any cell type, making them a powerful tool to study development and disease. However, most existing cell lines aren't suited to study sex differences. In collaboration with AstraZeneca, Turner lab researchers Ruta Meleckyte and Wazeer Varsally addressed this by creating new iPSCs with either XX (female) or XY (male) sex chromosomes. All other chromosomes were identical, so any differences observed can be linked to sex. These openly available iPSCs will enable more accurate modelling of sex-specific biology and may help in developing better, more personalised treatments in the future.

In this study, researchers at the Crick and UCL investigated how an epigenetic change called DNA methylation cooperates with genetic changes in non-small cell lung cancer (NSCLC) using 217 tumour and normal regions from 59 TRACERx patients. This is the first multiregional lung cancer cohort integrating genomic, transcriptomic, and epigenomic data to map tumour evolution in such detail. They uncovered a novel mechanism, where DNA methylation fine-tunes how oncogenes are switched on together by compacting the DNA. We also identified hypermethylated driver genes emerging early in tumour evolution and developed a new metric, Mr/Mn, to distinguish functional from passenger methylation changes. Our work highlights epigenetic drivers with therapeutic potential.

Several models of cell fate lineages have been presented, some proposing a traditional straight path and others a more dynamic model, where cell fate remains more flexible. Researchers at the Crick combined a range of experimental techniques - single cell transcriptomics, quantitative live cell imaging and mathematical modelling - to track cell fate and determine which path is the right one. They found that there was no singular path, and these theories were not competing explanations but complementary snapshots of human development. The team also observed the influence of two important signalling molecules, Activin and BMP4, in determining which route cells would take between mesoderm or endoderm layers.

In a joint effort from the Francis Crick Institute, UCL and the Netherlands Cancer Institute, researchers have demonstrated that lung cancers consist of different subclones that differ intrinsically in their capacity to evade immune attack. Cancers are genetically heterogeneous – consisting of different subclones – but to what extent this affects immune evasion remained largely unclear. Now, using samples from the TRACERx cancer evolution study, the team have established organoids – mini-tumours growing in 3D - from different regions from the same tumour, and further separated these into individual subclones. Challenging these with immune cells from the patient’s tumour showed that different subclones isolated from the same tumour differ profoundly in their ability to trigger an immune response. This provides direct functional evidence that subclonal cancer evolution has important consequences for the ability to evade immune attack.

Researchers at the Francis Crick Institute have developed a new stem cell model of the mature human amniotic sac, which replicates development of the tissues supporting the embryo from two to four weeks after fertilisation. The new 3D model – called a post-gastrulation amnioid (PGA) – closely resembles the human amnion and other supportive tissues after gastrulation. The team developed PGAs by culturing human embryonic stem cells in a series of steps with just two chemical signals over 48 hours, after which the cells organised themselves into the inner and outer layers of the amnion. A sac-like structure formed by day 10 in over 90% of the PGAs, which expanded in size over 90 days. The researchers showed that a transcription factor called GATA3 is necessary to kick-start amnion development and that signals from the amnion can communicate with embryonic cells to stimulate growth. Finally, they believe PGAs could also provide an alternative source of amniotic membranes for medical procedures like cornea reconstruction.

Research led by a team of scientists at Francis Crick Institute and clinicians at Imperial College London investigated whether changes in certain circulating immune cells (neutrophils) were detectable in newly diagnosed patients with breast cancer. The team recruited women that, after routine mammograms and subsequent biopsy, were diagnosed with breast cancer. Their disease was very early stage and asymptomatic. The researchers collected blood before treatment, isolated and analysed circulating neutrophils (one of the more abundant immune cells in blood) and compared it to neutrophils from age matched healthy volunteers.

The results showed that different cancer specific activities in the cells were detectable in circulating neutrophils from early cancer patients compared to healthy volunteers. These activities were not detected in patients with benign breast disease. This study only included a limited number of patients, but it represents proof-of-concept evidence suggesting that disruption to neutrophils occurs very early in the disease. Defining these disruptions could represent not only a way to understand how they contribute to tumour progression, but also could be exploited as biomarkers for early disease.