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 UCL and the Francis Crick Institute have, for the first time, identified the origin of cardiac cells using 3D images of a heart forming in real-time, inside a living mouse embryo. The team used a technique called advanced light-sheet microscopy on a specially engineered mouse model, where a thin sheet of light is used to illuminate and take detailed pictures of tiny samples, creating clear 3D images without causing any damage to living tissue. They were able to track individual cells as they moved and divided over the course of two days – from a critical stage of development known as gastrulation through to the point where the primitive heart begins to take shape. This allowed the researchers to identify the cellular origins of the heart. The study’s findings could revolutionise how scientists understand and treat congenital heart defects.

The initiation of DNA replication occurs at tens of thousands of sites on the human genome during every S phase, but in the absence of any consensus DNA sequence, it is unclear how these sites are specified. Researchers at the University of Cambridge and the Crick identified sites with increased density during quiescence and G1 phase that overlap with DNA replication origins. The increased density derives from changes made by enzymes at these sites, and inhibition of these enzymes reversibly prevented DNA replication and cell proliferation. These findings provide a mechanism for the epigenetic specification and semiconservative inheritance of DNA replication origin sites, and for the once-per-cell cycle control of origin activation.

Researchers at the Crick and the University of York with clinicians from Great Ormond Street and Guy’s and St Thomas’ Hospitals have investigated all the kinase enzymes expressed (the kinome) in children with a disease called Multiple Endocrine Neoplasia Type 2 (MEN2), to identify new therapeutic markers and targets. This autosomal dominant disease leads to several cancers including the development of thyroid cancer and is caused by pathogenic variants in the receptor tyrosine kinase RET. But the development and progression of these tumours are not always predictable, even within families with the same RET pathogenic variant. This study identified MEN2 subtype and RET pathogenic variant-specific alterations in signalling pathways including mTOR, PKA, NF-κB and focal adhesions, each of which were subsequently validated in patient thyroid tissue.

Organisms grow through the division of the cells that make up our bodies. As well as growth, cell division is also essential for different types of cells to decide what cell type they will become (from different neurons in our brains to the cells that line our guts). How cells divide therefore needs to be tightly controlled both in space (so that the daughter cells after division end up in the right place) and in time (so that daughter cells make the correct choice of what to become). To make this process even more complicated, each cell type is very different in terms of shape, behaviour etc…, so cell division must adapt to the needs of each tissue, an aspect of biology we know very little about. Researchers at the Crick have found a protein called Meru (called after the Bengali word for “polar”) that can tell a cell in which direction and when to divide. Meru is located at one of the poles of a cell type called the sensory organ precursor and allows this cell to orient itself in the tissue and to time its division just right to allow both daughter cells to create the right structure.

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.

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.

In this work, Jones and colleagues shed light on the role of a highly conserved yet poorly understood gene, FAM83F. This gene has been linked with human cancer, yet very little is known about its function. Using zebrafish embryonic development as a model, they show that loss of FAM83F leads to impairment of the mechanism by which cells clear away and degrade cellular materials. Mutant zebrafish embryos are more sensitive to stress caused by DNA damage and hatch prematurely. These findings have implications for our understanding of the role of FAM83F in both development and disease.