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.

Researchers at the Crick and UCL Queen Square Institute of Neurology have shown that alpha-synuclein, the protein that aggregates in Parkinson’s disease, can trigger widespread RNA editing in astrocytes as part of an anti-viral innate immune response. They used human stem cells to generate astrocytes, the most abundant cell type in the brain. Using molecular biology, genomic and computational approaches, they showed that forms of alpha-synuclein trigger the same innate immune pathways in astrocytes that viruses do. One consequence of this response was a marked increase in RNA editing, with extensive changes throughout the genetic code as it is converted into proteins.

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 have found that the small intestine grows in response to pregnancy in mice. This partially irreversible change may help mice support a pregnancy and prepare for a second. They found that pregnant mice had a longer small intestine from just seven days into the pregnancy. By the end of the pregnancy, around day 18, the small intestine was 18% longer, and it remained longer up to 35 days after lactation. The villi and crypts inside the small intestine also became longer and deeper at the same time, but returned to pre-pregnancy values just seven days after weaning. The researchers identified an increase in a membrane protein called SGLT3a early in pregnancy. This sodium and proton sensor was responsible for about 45% of the villi growth triggered by reproduction but wasn't necessary for entire small intestine lengthening. The team believe hormones may play a role in switching on the gene for SGLT3a.

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.

Nuclear Magnetic Resonance (NMR) spectroscopy helps scientists understand how proteins are structured and behave. While NMR commonly focuses on the backbone and methyl-bearing side chains of proteins, analysing aromatic side chains, often crucial for protein function, is more difficult. To overcome this, researchers at the Crick and UCL developed a deep learning tool named FID-Net-2. By combining innovative developments in biomolecular NMR with advanced deep learning, FID-Net-2 substantially enhances the quality and resolution of NMR data for aromatic side chains. This allows insights into the mechanism of protein dynamics like folding. This approach works across various protein sizes and promises to improve NMR analysis in structural biology.