Changes in circulating immune cells may be able to reveal the presence of breast cancer
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.
Targeting the interplay between HIF and mTOR in kidney cancer
The HIF and mTOR signalling pathways are frequently dysregulated in cancer. In the most common kidney cancer, clear cell renal carcinoma, HIF is upregulated, and mTOR is hyperactivated, but their interplay is poorly understood, in part because of difficulties in simultaneous measurement of global and mRNA-specific translation. Yoichiro Sugimoto and Peter Ratcliffe describe a new method, high-resolution polysome profiling followed by sequencing of the 5′ ends of mRNAs (HP5), that addresses this challenge, and use it to analyse the interplay of HIF and mTOR in kidney cancer cell lines. They show that specific classes of HIF1A and HIF2A target genes have different sensitivity to mTOR, in a manner that suggests combined use of HIF2A and mTOR inhibitors is a rational therapeutic strategy for kidney cancer.
Published in Nature Structural and Molecular Biology
Modelling and enhancing migration of hiPSC-derived myogenic progenitors
Cell therapies to treat severe muscular dystrophies are inefficient. Major hurdles include the limited ability to expand mature myogenic cells in vitro, as well as the minimal migration capacity of myogenic cells upon transplantation, which inhibits dispersal into affected tissues. Researchers in the Tedesco lab have used directed iPSC differentiation, single-cell profiling, microfluidics and 3D tissue engineering to show that hiPSC-derived muscle satellite stem cells, which may be useful in cell therapies for muscular dystrophy, can have their in-vivo migration enhanced through activating the NOTCH and PDGF pathways, via treatment with DLL4 and PDGF-BB.
Gene discovery in a spectrum of severe birthmark diseases leads to patient benefit
Serious multisystem conditions where children born with speckled pigmented and/or vascular birthmarks, as well as variable involvement of the central nervous system, asymmetrical growth and a predisposition to cancer, have until now been poorly understood and untreatable. A large international team led by the Kinsler lab has shown that this disease spectrum is caused by mosaicism—where some cells in an individual are mutated and some are normal —involving mutations of the PTPN11 gene which hit the developing baby during pregnancy. Laboratory studies demonstrated that cells with the PTPN11 mutations cause abnormal blood vessel formation, compared to normal cells, and demonstrate overactivation of a signalling pathway known to lead to cell abnormalities and cancer, including melanoma. Importantly the authors have identified that PTPN11-mosaic patients risk passing the mutation in germline (whole body) form to their children, who could then develop a serious multisystem disorder called Noonan syndrome with lentigines. Identification of the faulty gene means that patients can now be screened for the mutations by having a biopsy of the birthmarks, meaning that cancer risk and potential transmission to the next generation can be better understood and managed.
In healthy cell division, the replicated DNA forms sister chromatids that must remain connected until separation later in the process. It’s only then that X-shaped chromosomes must be segregated symmetrically: each sister chromatid (one half of the X) is pulled to the opposite edges of the dividing cell by microtubules - protein filaments that generate force – to give rise to two daughter cells with an equal amount of genetic material. A ring-shaped protein called cohesin physically links sister chromatids and, like an elastic band, resists the forces generated by microtubules. Not only is the absence of cohesion lethal, but mutations in it can lead to cancer and incurable developmental disorders.
In this research by the Molodtsov and Uhlmann groups, the force that the cohesin complex can withstand is revealed. Using optical tweezers, the researchers pulled apart the DNA molecules tied by cohesin, showing that one cohesin ring is capable of embracing two DNAs and can resist up to 20 piconewtons of force, and when it breaks, it always opens at its weakest point: the hinge domain. These findings reveal that 40 cohesins are sufficient to oppose the tension generated in mitosis, whilst larger forces release the sisters. For the first time, this work lifts the veil on cohesin’s physical properties, bringing us closer to understanding how it is dysregulated in disease.
Published in Nature Structural and Molecular Biology
Specific inhibition in the neocortex
The brain’s neocortex contains both excitatory and inhibitory neurons, with inhibitory neurons thought to regulate and coordinate the activity of excitatory cells. Inhibitory neurons were thought to make dense non-specific connections with nearby excitatory cells.
However, researchers at the Francis Crick Institute as well as at the Sainsbury Wellcome Centre at UCL and the Biozentrum at the University of Basel have found that parvalbumin-positive (PV+) neurons, a major subtype of inhibitory cells, strongly inhibit a subset of nearby excitatory cells that provide them with strong excitatory inputs. By characterizing the response properties of PV+ neurons in the visual cortex and measuring the strength of their connections, they found that PV+ specifically made strong connections to those excitatory cells that had similar visual responses. This may play an important role in maintaining stable network activity and preventing uncontrolled firing of excitatory neurons.
A study led by the Bonnet lab looks at how acute myeloid leukemia cells interact with and alter bone marrow. The team has produced an omics repository of potential biomarkers for different bone marrow cell populations.
Ed Tate and Wouter Kallemeijn in the Chemical Biology and Therapeutic Discovery Satellite Lab at the Francis Crick Institute and Imperial College London, in work led by Jesus Gil at the MRC-LMS (Laboratory of Medical Sciences) at Imperial College, have uncovered critical insights that can pave the way for novel therapeutic approaches to tackle cancer, fibrosis, and many age-related conditions. Ed and Wouter identified and patented NMT inhibitors to selectively kill senescent cells, which have stopped growing but can drive inflammation in cancer and fibrosis. Crick/Imperial spin-out Myricx Bio is now developing NMT inhibitors as potential senolytic drugs.
Cell polarisation is a fundamentally important ordering process that breaks the internal symmetry of a cell by establishing a preferential axis. The Goehring lab used the nematode worm C. elegans to study why the polarity protein PAR-3 needs to aggregate to efficiently move to the front of the worm embryo. Contrary to previous theories, they found that the size of molecule aggregates did not directly affect PAR-3 movement. Instead, what matters is how tightly these molecules stick to the membrane. This discovery challenges existing ideas about cell transport mechanisms and highlights the role of membrane stability in cellular processes. Defects in cell polarisation can disrupt numerous processes, so developing a systems-level understanding may enable new therapies for developmental defects and cancer.
New tool to control of fruit fly gene expression using light
Researchers in the Vincent Lab, , in collaboration with the group of Yohanns Bellaiche at Institut Curie in Paris, have developed a new tool for robust control of gene expression in Drosophila using light. They successfully used the new method to activate key genes in different tissues and at various developmental stages and demonstrated gain and loss-of-function phenotypes at animal, organ, and cellular levels. Their work provides developmental biologists with the ability to control gene expression with high temporal and spatial resolution, a valuable addition to the Drosophila genetic toolkit.
Lysosomes are cellular organelles containing a potent cocktail of digestive enzymes—proteases—used to break down worn out cell parts and destroy invading viruses and bacteria. There is crosstalk between lysosomes and mitochondria, the energy generating organelles of cells, but whether this cross talk is affected by lysosomal damage is unknown. In a collaboration led by the Gutierrez lab, Bussi et al uncovered a pathway whereby protease leakage from functional lysosomes degrades mitochondrial proteins and impairs human macrophage metabolism, relevant to several diseases where compromise of the lysosomal membranes is a key intracellular event. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprogramming after membrane damage to the network of intercellular organelles.
A study from the Briscoe lab has developed methods to quantify so-called Waddington landscapes, a description of cellular differentiation. The team have constructed a dynamical geometric model that can predict cell fate.
During development, multicellular organisms undergo stereotypical patterns of tissue growth in space and time, but how this is orchestrated remains unclear, largely due to the difficulty of observing and quantitating this process in a living organism. The Tapon and Salbreux labs used live imaging and computational methods to quantitatively analyse developmental growth in the fruit fly adult abdominal epidermis. Abdominal growth is initiated by degradation of the basement membrane to which the epidermal progenitor cells are attached and is terminated by rapid exit from the cell cycle, rather than a gradual slowdown, as occurs in some other tissues. Different developing tissues can therefore achieve their final size using distinct growth termination strategies.
Uncovering cancer-immune system interactions could inform how patients respond to immunotherapy
Researchers at the Francis Crick Institute and King’s College London have revealed the complex interactions between cancer and the immune cells that surround a tumour, with the potential to inform how patients will respond to immunotherapy. The researchers analysed thousands of samples across 32 types of cancer to examine the way that cancer dynamically interacts with the tumour immune microenvironment (TIME), allowing the disease to flourish.
Focusing on a class of genes called cancer drivers, they identified 477 of these cancer drivers that interact with multiple features of the TIME, suggesting that they drive the formation of cancer by disrupting biological processes within the cell as well as interfering with the immune system.
Using theory from engineering to understand how different cells are generated in a tissue
Researchers at the Crick have proposed a new way to analyse how signals control patterns of gene expression during embryonic development. In many developing tissues, signals known as morphogens form gradients across tissues. The current view, the “French Flag” model, suggested that cells simply read morphogen concentrations directly to determine their fate. However, in many tissues, morphogen levels change dynamically over time, concentration does not correlate with position and the duration of signalling influences patterning.
The researchers at the Crick used tools from optimal control theory to determine signalling strategies that optimally drive cells to their correct identity. They found that cells exploit the underlying behaviour of gene networks to make cell fate decisions. The signalling adapts over time, providing a large push early on but then backing off as the cell approaches its target state. This offers insight into the principles that produce cell fate decisions during embryonic development, explaining how the right type of cells are produced in the correct positions.
Common dietary supplement could protect against Cryptosporidium parasite infection
Researchers at the Francis Crick Institute have discovered that a common dietary supplement could protect against chronic Cryptosporidium infections which are particularly prevalent in children under two and in areas with poorer sanitation. The researchers exposed mice to the Cryptosporidium parasite and observed that infection triggered an expansion of immune cells in the intestinal epithelium, which are part of the first line of defence against the parasite. When these CD8+ T cells were transferred to mice with weakened immune systems, the researchers saw that the mice were now able to fight off Cryptosporidium infection. Mice that lack the AHR receptor, or healthy mice fed a diet specifically deficient in indoles, had a reduced population of intestinal CD8+ T cells. This meant the mice were less able to fight off the infection, and showed that CD8+ T cells are reliant on the AHR system to protect the intestine.
Gene-editing used to create single sex mice litters
Researchers in the Turner lab, in collaboration with the University of Kent, used gene editing technology to create female-only and male-only mice litters with 100% efficiency. Targeting the Top1 gene, which is essential to DNA replication and repair, their method uses CRISPR-Cas9 to induce sex-linked lethality before embryo implantation, allowing only the desired sex to develop. This proof of principle study demonstrates how the technology could be used to improve animal welfare in scientific research and perhaps also agriculture.
New method to understand protein biomarkers in plasma
In recent years, the Ralser lab have developed new methods to understand proteins in plasma – the liquid part of the blood – with the hope of discovering new protein biomarkers, which are indicators for a wide range of diseases.
However, the structure and function of proteins is highly influenced by chemical modifications. One such modification – glycosylation – happens to lots of different proteins in plasma and is known to be altered in diseases such as cancer. Currently, methods to study protein glycosylation in plasma are relatively limited, generally requiring additional handling steps. The team developed a method capable of quantifying over a thousand glycopeptide features from human plasma without any extra steps, making it compatible to understanding data from large clinical trials.
They then applied this method to a cohort of COVID-19 patients and healthy donors, finding changes in glycosylation of plasma proteins in response to increasingly severe COVID-19. They hope this method can be applied for larger epidemiological and clinical studies, both to better understand the underlying biology and develop new biomarkers.
Coupling cell division and polarity to keep cells organised
The vast majority of cells exhibit ‘cell polarity’ – they typically must distinguish their tops from their bottoms and their front from their backs. In complex organisms like animals or humans, cell polarity must be coordinated between cells to generate functional tissues and organs. Such coordination poses a challenge during embryonic development or in regenerating tissues as cells are continuously growing and dividing. To ensure cells are oriented correctly with respect to one another, cell polarity and cell division must be coupled.
When a cell divides, it generates a flow of material towards its centre, which aids the process of cell division and contributes to the forming boundary between what will become the two new daughter cells. Here the researchers show that this flow of material also transports a key molecule, PAR-3, into this forming boundary. The local flow-dependent accumulation of PAR-3 breaks the internal symmetry of the daughter cells and ensures that the polarity of each daughter cell is oriented properly with respect to its sister. This simple physical mechanism for coupling cell division and polarity may be a general method for keeping cells organised in actively dividing tissues.
Diversity of stem cells and selective maintenance of descendent cells in the mouse pituitary gland
In organs with a high cell turnover, stem cells often generate new cells to maintain cell numbers and organ function. In contrast, in organs with a low cell turnover, such as the pituitary gland, stem cells are quiescent (i.e. dormant) and only generate new endocrine cells in exceptional circumstances. For example, upon removal of a pituitary target organ, such as the adrenals, stem cells are activated and some give rise to new corticotrophs, the endocrine cell type that normally regulates these glands.
In this study, the researchers explored quiescent and activated pituitary stem cells using single cell technologies, uncovering subtypes of stem cells in different regions of the gland. They unexpectedly observed that activated stem cells generate a wide range of endocrine cell types in addition to those regulating the removed organ. Analysing these new stem cell-derived cells at different times and with different tools, they found that only required cells, such as corticotrophs after adrenal removal, are maintained. This system provides a good model to characterise stem cell activity and how both emergence and maintenance of new cells is regulated.