Publication highlights

Researchers at the Crick and UCL have shown that reported that astrocytes show signs of hypoxic stress long before neurons begin to die in ALS. Using stem cells from patients to generate astrocytes carrying ALS-linked mutations in a gene called VCP, which is linked to inherited forms of ALS, the team showed that astrocytes exhibited clear signs of 'pseudo-hypoxia'. This meant they had switched on a low-oxygen response despite being in normal oxygen conditions. This was driven by HIF-1a, a master regulator of how cells respond to oxygen. Instead of being degraded under normal conditions, it had accumulated in the nucleus and activated genes involved in metabolism, energy production and stress responses. As a result ALS astrocytes showed mitochondrial dysfunction and a reduced ability to support motor neurons. This is particularly exhibited as an inability to correct the mislocalisation of RNA-binding proteins, a well-known molecular hallmark of ALS, compromising neuron survival.

Natural ion channels of biology allow cells to communicate, transfer nerve impulses, trigger sensations, and cellular processes. Biology has a variety of highly effective channels, but creating new, orthogonal systems is challenging. Researchers at the Crick have designed a system able to span a lipid bilayer, with a single internal channel, which allows the passage of certain anions and cations. They can control its activity using three biorthogonal handles - light, pH, and presence of a 'guest' molecule, which blocks the channel. This allows them to formulate a molecular logic gate, achieving a simple analogy of the complex functions of biological transmembrane proteins.

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.

Researchers at the Francis Crick Institute, King’s College London and the University of Fribourg have developed polymer water channels, similar to commonly used plastics, that can draw salt out of water, inspired by the body’s own water filtering system. If their innovation could be scaled up and produced industrially, this could help to filter seawater to create drinking water. The new channels mimicked aquaporins, proteins that rapidly transport water across cell membranes while excluding salt, and were organised into a helix structure called polymers or into cyclic structures called macrocycles. The pores inside the two types of channels were filled with a chemical mixture of fluorine and molecules called hydrocarbons, which together create a greasy layer. Through a series of experiments, the team confirmed that the channels actively transported water across a membrane and excluded salt.

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.

The NanoBiT Biochemical Assay was created to investigate protein-protein interactions in live mammalian cells. Soly Ismail, Scientific Programme Manager in the Oncogene Biology Laboratory, led by Julian Downward, further developed the assay so it only needed to use parts of a extracts from cells rather than the live cells themselves, allowing it to be scaled up to undertake many tests at once. These protein-protein interactions are often difficult to visualise but could be potential new drug targets. Soly used the assay to detect and block weak interactions between a cancer-causing protein called RAS and an enzyme called PI3kK. The identified compounds that bind with PI3kK will be followed up in further tests to understand the nature of these interactions and how to optimise these compounds for drug development. Soly was awarded the Sir David Cooksey Prize in Translation for this work.

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.