National Mouse Genetics Network

The Medical Research Council (MRC) is investing more than £20m in a major new network in mouse genetics for disease modelling to accelerate our understanding of human disease and improve diagnosis and treatments. Here, Professor Owen Sansom, Director of the National Mouse Genetics Network, writes about his vision for the new network, the exciting opportunity for the UK, and plans to engage with the community.

Publication Highlights: September 2020

Luke Tweedy, Robert Insall and colleagues at the Beatson report in Science ("Seeing around corners: Cells solve mazes and respond at a distance using attractant breakdown") that cells navigate complex environments such as man-made labyrinths by following and leaving chemical 'breadcrumbs', allowing pursuing cells to instantly find the shortest path and to avoid dead ends. This study helps us to understand how the environment and signals produced by other cells cue the direction of cancer spread.

Rob Wiesheu, Seth Coffelt and co-authors have made a pre-print available on BioRxiv ("Ly6C defines a subset of memory-like CD27+γδ T cells with inducible cancer-killing function"), which identifies a new subset of γδ T cells in mice that are similar to mature γδ T cells in humans. Culturing these cells stimulates their cancer-killing activity and opens up interesting opportunities for anti-cancer immunotherapy.

Chatrin Chatrin, Mads Gabrielsen, Danny Huang and Glasgow scientists describe a mechanism where ubiquitin itself becomes a target for post-translational modification ("Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases"). When binding NAD+, Deltex family E3 ligases facilitate the addition of ADP-ribose to ubiquitin (ADPr-Ub). This reversible process makes ubiquitin unavailable to the ubiquitin cascade and its associated regulatory machinery. The physiological role of ADPr-Ub, however, remains to be determined.

Together with their co-authors, Rafael Martinez and Hing Leung have distributed a preprint on BioRxiv ("Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer") that provides large-scale analyses of proteins underlying three distinct castration-resistant prostate cancer models (CRPC). Although they identify distinct proteomic landscapes, SLFN5 is found at high levels in all models and is connected to poor outcome in patients. Mechanistically, SLFN5 changes the availability of metabolic building blocks in cells affecting a growth pathway underlying cancer.

Anna Koessinger, Dominik Koessinger, Jim Norman, and Stephen Tait together with other Glasgow cancer researchers ("Quantitative in vivo bioluminescence imaging of orthotopic patient derived glioblastoma xenografts") showcase a new technique to monitor long-term tumour growth in patient-derived glioblastoma models. Through imaging the overexpression of near-infrared fluorescent protein they have developed a method that is rapid, accurate and has clear advantages over conventional approaches.

Jacqueline Tait-Mulder, Alexei Vazquez together with Beatson Proteomics scientists link formate – its metabolism is increased in some cancer types – to the production of pyrimidine through the mTORC1 facilitated phosphorylation of CAD ("The conversion of formate into purines stimulates mTORC1 leading to CAD-dependent activation of pyrimidine synthesis"). How these events are linked to the tumour's higher demand for formate will need to be determined in future work

David Bryant and colleagues have shared a pre-print on BioRxiv ("Spatial enrichment of phosphoinositide metabolism is a molecular switch to promote metastasis") where they identify the protein IQSEC1 as a molecular mechanism to communicate to cancer cells whether to grow at the tumour site or become invasive and spread around the body. IQSEC1 directs the production of cellular messengers (phosphoinositides) to areas of the cells where forward stretching, invasive projections are formed. With the potential to reduce cancer spread, the inhibition of IQSEC1 makes an interesting target for potential therapeutic intervention.

CRUK Commercial Partnerships publishes its 2019/20 Annual Review

CRUK Commercial Partnerships acts as the meeting point between the charity's funded research and industry. It helps to accelerate the translation of research into products for patient benefit through the development and commercialisation of exciting new discoveries. In addition, any revenue received through its commercial partnerships is reinvested back into developing lifesaving research.

This annual review aims to demonstrate the commitment of Commercial Partnerships over the last year to the researchers whom it supports with achieving their translational ambitions, the companies with whom it partners and the cancer patients to whom its efforts are ultimately dedicated.

Over the last financial year, Commercial Partnerships supported CRUK researchers to learn entrepreneurial skills, file 38 patents, create two spinout companies and re-invested £43 million back into cancer research. This includes scientists at the Beatson (page 23 of report).

Read the full report icon CRUK CP Annual Review 2019/20 (10.57 MB)

Publication Highlights: August 2020

Patients affected by recessive dystrophic epidermolysis bullosa often develop life-threatening, aggressive skin cancer (SCCRDEB) with limited treatment options. Jasbani Dayal, Gareth Inman and colleagues found that although the response to blocking endogenous TGFβ signalling was diverse in SCCDREB samples, the treatment predominantly stopped cancer cell proliferation (in British Journal of Dermatology). This offers potential therapeutic benefits to these patients but clinical trials will need to proceed with caution due to the tumour-proliferative effects seen in a small number of patients.

Shashi Singh, Rob Insall and co-authors showed that the Scar/WAVE complex - a key driver for the formation of finger-like protrusions at the front edge of a cell – is phosphorylated after its activation, thus is not required for its activity. However, upon sensing physical adhesion, cells with phosphorylated Scar/WAVE complex demonstrated altered dynamics and size of projections, changing the cell's migration speed ("Cell–substrate adhesion drives Scar/WAVE activation and phosphorylation by a Ste20-family kinase, which controls pseudopod lifetime"). Investigating how cells move is important for understanding how cells travel in a physiological context such as cancer spread.

Alba Roca, Stephen Tait and other Beatson scientists found that "Venetoclax causes metabolic reprogramming independent of BCL-2 inhibition". The BH3-mimetic drug Venetoclax diminished mitochondrial function and inhibited the TCA cycle, a key biochemical reaction to release stored energy, through a mechanism not involving BCL-2. Although the authors observed mitochondria with an unusual shape and upregulation of the cell's integrated stress response in the drug-treated cells, the metabolic effects of Venetoclax on cells needs to be investigated further. 

Together with other Beatson scientists, Syed Feroj Ahmed and Lori Buetow showed that the E3 ubiquitin ligase DTX2 recruits proteins commonly involved in DNA damage repair via the domain on its C-terminal (DTC). While PAR-modified proteins interact with DTX2 at an ADP-ribose-binding pocket at DTC, the RING domain facilitates substrate ubiquitination. This study establishes another mechanism of cross-talk between protein modifications, as seen for other signalling pathways.

Update on our volunteers

02 September 2020

Beatson scientists continue to support and volunteer at the University of Glasgow's Lighthouse Lab COVID-19 testing centre. Over 20 scientists from 12 of the Institute's different research groups and advanced technologies teams have volunteered their expertise, day and night, and the Lighthouse Lab team has recently passed the milestone of over 1,000,000 samples processed.

Although many of these scientists are now returning to cancer research, the CRUK Beatson Institute remains incredibly proud of those who volunteered to establish, manage and work in the Lighthouse Lab and those who continue to do so.

UoG Lighthouse Lab volunteers

July 2020 Publication Highlights

31st July 2020

Jamie Whitelaw, Karthic Swaminathan, Laura Machesky and co-authors show in their study in Cells that the WAVE regulatory complex (WRC) is required for cell mobility, as seen for example in cancer spread. When one of WRC's components, Nckap1, was deleted, cells were unable to form sheet-like projections at their front edge and the turnover of their anchoring system was reduced, resulting in the slowing down of the cells' forward speed. This demonstrates a clear role of WRC in the ability of cells to migrate.

Florian Bock, Stephen Tait and colleagues at the Beatson Institute made a pre-print available on bioRxiv – "Apoptosis-induce FGF signalling promotes non-cell autonomous resistance to cell death" - which describes how dying cells alert their neighbours by releasing the signalling protein FGF2. In response, the surrounding cells upregulate their survival machinery, protecting themselves from cell death. Understanding this process is important to help us to make anti-cancer therapies more efficient and avoid the development of treatment resistance. 

Together with fellow scientists from the Beatson Institute, Sandeep Dhayade, Matthias Pietzke and Alexei Vazquez investigated the impact of formate supplementation in their publication in Nutrients. It found that nutritional intervention with formate has sex-specific effects on body weight and the gut microbiota in mice. Further work will be required to determine the role of formate supplementation in humans. 

Another publication by Matthias Pietzke and Alexei Vazquez – "Metabolite AutoPlotter - an application to process and visualise metabolite data in the web browser" - introduces a user-friendly online tool that reads and processes high-throughput metabolite data to generate high-quality, individual plots. The online application is under constant development and the developers will responds to users' feedback and suggestions. 

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