Publication highlights

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.

If a tightly packed layer of epithelial cells gets overcrowded, excess cells are extruded, causing them to die. To find out how the body decides which cells are extruded, researchers at the Crick and King's College London set up live imaging of overcrowded epithelial cells under a microscope. They found that overcrowding triggers sodium channels on epithelial to open, bringing in salts and depolarising the cells. The strong ones can pump the sodium back out, repolarising themselves, but weak ones without energy can't, using a 'last gasp' of energy to activate a current that results in water rushing out of the cells, causing them to shrink and extrude.

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.

Researchers at the Crick and UCL have shown that genetic messages, called mRNAs, are misplaced in nerve cells in a model of Alzheimer's disease and frontotemporal dementia. They looked at corticial neurons specialised from skin cells from people with inherited forms of Alzheimer's disease or FTD who had mutations in APP or PSEN1 genes (Alzheimer's disease) and VCP (FTD). Between 82 and 140 mRNAs were found in a different place in the neurons with the mutations compared to control neurons. These included ten that were common to both diseases, all found to carry messages from genes related to mitochondrial function. The team also found that mitochondrial DNA was leaking out of the mitochondria, and that diseased neurons had fewer and smaller mitochondria. Treating these cells with a drug called ML240 returned the misplaced mRNAs to their typical locations, reduced the amount of mitochondrial DNA leakage and raised mitochondrial activity back to normal levels.

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.

Researchers at the Crick and NPL, as part of the CRUK Grand Challenges team Rosetta, have developed a multimodal imaging pipeline that extends upon the principles of correlative light, electron, and ion microscopy (CLEIM), which combines confocal microscopy reporter or probe-based fluorescence, electron microscopy (EM), stable isotope labelling and Nanoscale secondary ion mass spectrometry (NanoSIMS). Their protocol allows an unprecedented extraction of biological information from specimens, whilst being based on a series of well-established and widely available technologies, thus allowing quick adaptation of the protocol for individual research needs. This integration provides a multifaceted view of the tissue microenvironment, capturing both the internal cellular architecture and the intricate metabolic dynamics occurring within. The researchers tested their pipeline by imaging the incorporation of carbon from glucose into B and T cells in mouse liver tumours.

Loss of the tumour suppressor gene CDKN2A is a common early event in development of the pre-cancerous condition Barrett's oesophagus. Around 1% of Barrett's patients go on to develop oesophageal adenocarcinoma, but rather than enhancing this progression, as would be expected, early CDKN2A loss is actually protective. Having made this striking observation, the team at the Crick and collaborators showed that the reason lies with a second tumour suppressor gene, TP53. Loss of TP53 is a key driver of transformation into oesophageal cancer, but if CDKN2A is also missing, the Barrett's cells are too weakened to progress. CDKN2A changes sides to become a villain later in the process: if it's lost after the cancer has developed, it promotes a more aggressive tumour.

Researchers at the Crick and the UCL Cancer Institute have identified a genetic change which happens early in lung cancer development, that makes cancer cells divide abnormally and become harder to treat. They studied non-small cell lung cancer samples from the Cancer Research UK-funded TRACERx study, to investigate which genetic changes make two hallmarks of cancer, chromosomal instability and whole genome doubling, more likely. They identified that a gene called FAT1 was mutated in lung cancer cells with unstable chromosomes before they doubled their genomes. Cells with a complete loss of FAT1 couldn’t divide properly to produce two new cells. When FAT1 and another gene involved in cell size regulation called YAP1 were removed, the cancer cells no longer doubled their genomes. This suggests that drugs that block YAP1 could be particularly effective against cells with high levels of chromosomal instability.

Scientists at the Crick have generated human stem cell models which, for the first time, contain notochord – a tissue in the developing embryo that acts like a navigation system, directing cells where to build the spine and nervous system (the trunk). The team first analysed chicken embryos to understand exactly how the notochord forms naturally. By comparing this with existing published information from mouse and monkey embryos, they established the timing and sequence of the molecular signals needed to create notochord tissue. With this blueprint, they produced a precise sequence of chemical signals and used this to coax human stem cells into forming a notochord. The stem cells formed a miniature ‘trunk-like’ structure, which spontaneously elongated to 1-2 millimetres in length. The scientists believe this work could help to study birth defects affecting the spine and spinal cord.