Dominika Kowalczyk and her Glasgow colleagues continued their work into the ubiquitination and degradation pathway of the tumour suppressor p53. In their recent article in Life Science Alliance, they described an intramolecular interaction between MDM2 and the tumour suppressor p14ARF that partially blocks the E2 binding site of MDM2 and therefore inhibits the MDM2-p53 signalling axis.
Together with fellow scientists at the University of Edinburgh, Kristina Kirschner's lab developed a new mathematical framework – built on longitudinal DNA sequencing data – to estimate the impact of mutations in clonal haematopoiesis genes on the growth potential of cells. In addition to identifying gene-specific effects on proliferation, they also suggested a time point for clinical follow up of patients who carry genetic mutations with significant fitness advantages. Read more in Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects
In a joint effort with the CRUK West of Scotland Clinical Trials Unit, Hing Leung and others reported on the findings of the SPECTRE trial, which investigated the effects of statins in combination with androgen deprivation therapy on castration resistant prostate cancer (CPRC). Although there was evidence that CPRC was stabilised, the treatment effects were below the required criteria to move the trial on to stage 2. The authors suggested that future studies should focus on the long-term effects of statin therapy together with standard-of-care treatment.
Mahnoor Mahmood and Payam Gammage, in collaboration with scientists at the Memorial Sloan Kettering Center in New York, reviewed the current understanding of cancer-associated mutations in mitochondrial DNA in Trends in Cancer. Although these mutations are abundant, recent technological advances now allow researchers to unveil the, so far unknown, functional significance of mtDNA variation.
In their study in Nature Metabolism, Emily Kay, Sara Zanivan and co-authors found that extracellular matrix production by cancer-associated fibroblasts - which is pro-tumorigenic - is under strict metabolic control, in particular as a result of increased proline synthesis.
Together with scientists at Imperial College London, the Coffelt lab published an article in Discovery Immunology which showed that γδ T cells with the receptor NKG2D acted to promote tumour growth in bowel cancer. The abundance of receptor ligands in the tumour microenvironment led to the accumulation of NKG2D-expressing cells and therefore the production of pro-inflammatory cytokines such as IL-17A.
Glycans are carbohydrate-based structures that determine the correct functioning of the cellular machinery. In PNAS, Alice Baudot, Victoria Wang and colleagues described the importance of appropriate glycan degradation for successful macroautophagy. When glycans accumulated, autophagy was slowed down due to impaired activity of lysosomal enzymes – resulting in accumulation of undigested cargo and failed fusion of the autophagosome-lysosome.
Beatson scientists were first to study the metabolism of bone marrow mesenchymal stromal cells cultured using Plasmax – a physiologically relevant medium developed in house by Saverio Tardito. The distinct exchange of glucose and glutamine carbons as well as citrate secretion from MSC helps shape the microenvironment in the bone marrow niche - "Mesenchymal stromal cells cultured in physiological conditions sustain citrate secretion with glutamate anaplerosis"
The team, which is led from Rutgers Cancer Institute of New Jersey, Weill Cornell Medicine and Cold Spring Harbor Laboratory, will receive £20m to take on the challenge of cancer cachexia, the debilitating wasting condition responsible for up to 30% of cancer-related deaths.
A world-class team of researchers, including the Beatson's David Lewis and the University of Glasgow's Oliver Maddocks, has been selected to receive a £20m Cancer Grand Challenges award to tackle the challenge of cancer cachexia. Cancer Grand Challenges is a global funding platform, co-founded by Cancer Research UK and the National Cancer Institute in the US, that supports a community of diverse, global teams to come together, think differently and take on some of cancer's toughest challenges.
The Cancer Grand Challenges CANCAN team, led by Rutgers Cancer Institute of New Jersey's Eileen White, Weill Cornell Medicine's Marcus DaSilva Goncalves and Cold Spring Harbor Laboratory Tobias Janowitz, will tackle the challenge of cancer cachexia – a debilitating wasting condition people often experience in the later stages of their cancer that imparts a poor prognosis and quality of life. Although cachexia is a major clinical problem, we understand very little about it and have no effective therapies for people who experience it. The team hopes to build a deep understanding of what causes cachexia and develop novel treatments to intervene – which could transform people's quality of life and ultimately survival.
"I'm ecstatic about being in such an exciting international, diverse and excellent team of scientists, all coming at the problem of cachexia from different angles," said co-investigator David Lewis. "The combination of backgrounds and approaches we bring has never come together for cachexia research before – we're approaching cachexia through a new lens of basic biology that will redefine what cachexia is and lay the foundation for new and varied treatments."
The CANCAN (Cancer Cachexia Action Network) team unites clinicians, advocates and scientists with expertise in cancer, metabolism, neuroendocrine function, immunology and more, across 14 institutions across the US and the UK, aiming to build the world's first virtual institute with a mission to solve cancer cachexia.
The CANCAN team, co-funded by Cancer Research UK and the National Cancer Institute, is one of four new teams announced on 16th June as part of Cancer Grand Challenges, representing a total investment of $100m to diverse, global teams to take on some of the toughest challenges in cancer research.
"Cancer is a global issue that needs to be met with global collaboration. This investment in team science encourages diverse thinking to problems like cachexia that have long hindered research progress," said David Scott, PhD, Director of Cancer Grand Challenges, Cancer Research UK. "Cancer Grand Challenges provides the multidisciplinary teams the time, space and funding to foster innovation and a transformative approach. CANCAN is one of 4 newly funded teams joining a scientific community addressing unmet clinical needs across cancer research."
Vasileios Papalazarou, James Drew and Beatson colleagues made a pre-print available that lends further evidence towards the idea that cancer cell behaviour can be influenced by sensing mechanical cues from the environment. Notably, pancreatic cancer cells, in response to a softer culture substrate, reprogrammed their gene expression, releasing factors to alter their own surroundings. In particular, the scientists found that the upregulation of collagen-VI and changes to the extracellular matrix ultimately encouraged the migration and invasion of these cells.
In their article in Developmental Cell, Kai Cao, Joel Riley and co-authors reported a link between impaired mitochondrial function and DNA damage. Dysfunctional, fragmented mitochondria engaged in a process called minority MOMP that triggers the activity of caspases which in turn leads to oncogenic DNA damage. They also suggested mechanisms by which a protein called BCL-2 could be targeted to prevent these cancer promoting signals.
In a multi-omics approach in iScience, Mark Salji, Hing Leung and others uncovered targetable pathways in models of castration-resistant prostate cancer (CRPC). Untargeted metabolomics revealed an accumulation of NAA and NAAG across different models of CRPC. Although additional work is required to evaluate the highlighted pathways, this study demonstrated the feasibility of a multi-omics approach for providing a data-rich resource for cancer research.
A study published in Cell Death & Differentiation by Tim Humpton together with Beatson scientists described a role for p53 in supporting the repair and recovery from acute liver damage. Through involvement of the detoxifying enzyme Cyp2a5/CYP2A6, p53 limited cell stress induced by reactive oxygen species and mediated regenerative processes – a function of p53 that also prevailed during chronic liver injury. As such, the authors suggested further investigation into Cyp2a5/CYP2A6 as a prognostic marker.
Today the MRC National Mouse Genetics Network is announcing a multi-million pound backing of mouse genetics for disease modelling. It will capitalise on the UK's international excellence in the biomedical sciences, creating 7 challenge-led research clusters.
The Network brings together experts from across the UK. The Mary Lyon Centre at MRC Harwell will act as the central hub of the Network, sharing access to specialist facilities, resources, data, and training with all other Network members. The partnerships established by the Network will enable integration of basic science research with clinical findings in order to accelerate our understanding of human disease and translation to patient benefit.
Prof Owen Sansom, Network Director & Director of the CRUK Beatson Institute:
"We're excited to announce this first set of research clusters forming the MRC National Mouse Genetics Network and to synergising our efforts to deliver impactful preclinical science through comprehensive sharing of data, resources, and expertise."
Dr Seth Coffelt, Prof Jen Morton and Prof Daniel Murphy are members of the Cancer Cluster led by Prof Karen Blyth at the CRUK Beatson Institute/University of Glasgow and Prof Louis Chesler at The Institute of Cancer Research, London. The Cancer Cluster is receiving ~£2.9 million of MRC investment and aims to use complex state-of-the-art mouse models to improve the understanding and treatment of cancer. The next generation of modelling will better replicate the complexity of the disease and more accurately predict therapeutic outcomes through the use of deep molecular phenotyping and novel strategies for generation of sophisticated mouse models which reflect all stages of disease progression.
Prof Karen Blyth, Co-Lead Cancer Cluster MRC Mouse Genetics Network:
"We are delighted to be part of the MRC National Mouse Genetics Network and have a fantastic team of scientists and clinicians within our Cancer Cluster eager to collaborate with the network and harness the opportunities this affords us for accelerating cancer discoveries to benefit patients"
Scientists as the camerawomen and -men of the unknown is the motto of a recently founded educational project. Bringing together art and science, Cell Worlds now stages an immersive experience in Bordeaux, France of the microscopic world of the human body – told through state-of-the-art fluorescent images by expert scientists like Dr Anh Hoang Le and Prof Laura Machesky at the Beatson.
Opening Event at the Cell Immersion exhibition in Bordeaux, France; right-hand installation shows work on melanoma cell migration by Anh Hoang Le Image Credit: Bertrand Bernager and Cell Worlds
One of the biggest showcases of scientific images, Cell Worlds brings together the works of 25 teams from world-renowned research institutes around the globe. Their aim - to awe the public with the beauty of, but also to introduce them to the complexity of life at cellular level. In a documentary style, their first project Cell Immersion features imagery of real live cells and explores how these single units of life move, hunt, divide and transmit information.
Prof Laura Machesky:
"I was delighted to be asked to contribute to Cell Worlds, along with Anh Hoang Le, whose beautiful microscope images attracted their attention. This is a real chance to communicate more broadly about the beauty of the cell as the most basic unit of life. It also highlights how rapidly our knowledge of biomedicine is advancing through technological breakthroughs in imaging."
Dr Anh Hoang Le and Prof Laura Machesky study the migration, invasion and metastasis of cancer cells and in particular how the proteins CYRI-A and CYRI-B influence the cells' ability to spread to distant sites. Within Cells Worlds you can follow their footage of two melanoma cell lines - one more invasive and one less invasive- mixed together, but migrating at different speeds; showing the aggressiveness of cancer cell migration.
The Cell Immersion installation can be visited in Bordeaux until the 2nd January 2023, but if you can't make it to France, maybe you can you spot some more of Anh's images in the documentary on YouTube?
Le AH, Yelland T, Paul NR, Fort L, Nikolaou S, Ismail S, Machesky LM. CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation. J Cell Biol. 2021;220.
Yelland T, Le AH, Nikolaou S, Insall R, Machesky L, Ismail S. Structural Basis of CYRI-B Direct Competition with Scar/WAVE Complex for Rac1. Structure. 2021;29(3):226-237.e224.