The Rho GTPase RAC1 is implicated in cell proliferation and is a potential target in cancer treatment. However, it is also required for normal intestinal homeostasis, so direct targeting of RAC1 could negatively impact that homeostasis. As an alternative approach to direct targeting, Karen Pickering, together with fellow authors, tested indirect targeting of RAC1 via other proteins that affect it, namely Vav2/3 and Tiam1 (A RAC-GEF network critical for early intestinal tumourigenesis). Deletion of all three of these genes profoundly suppressed hyperproliferation, tumourigenesis and RAC1 activity, and importantly, did so without impacting normal intestinal function.
MDM2 is a key regulator of the tumour suppressor protein p53 and is therefore another attractive drug target in cancer. However, designing inhibitors towards the protein's catalytic domain have been hampered by its tendency to aggregate. Here (Identification of a catalytic active but non-aggregating MDM2 RING domain variant), Helge Magnussen and Danny Huang identify a single point mutation that greatly decreases aggregation without affecting MDM2's catalytic activity. This variant should be very useful for developing drugs targeting the catalytic domain.
mTOR is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. Here (The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction), postdoc Ewan Smith and fellow authors use RNA-binding protein capture to identify changes in the RNA–protein interaction network following mTOR inhibition. They find that upon mTOR inhibition, the binding of LARP1 to numerous mRNAs increases, an interaction which the researchers show requires another protein, PABPC1. Importantly, they find that this binding results in translational repression of mRNAs encoding proteins critical for cell growth and survival.
Oncogenic KRAS mutations and inactivation of the APC tumour suppressor often co-occur in colorectal cancer. Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Here (The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer), postdoc Arafath Najumudeen and fellow researchers show that simultaneous mutation of Apc and Kras in the mouse intestine profoundly rewires cellular metabolism, increasing glutamine consumption. Importantly, the team show that SLC7A5, a glutamine transporter, is critical for colorectal tumourigenesis in models of both early and late stage metastatic disease. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS mutant colorectal cancer.
29th January 2021
We would like to extend a warm welcome to Professor John Le Quesne, who recently joined the Beatson Institute. John joins us from the MRC Toxicology Unit in Leicester, and he comes to Glasgow as Mazumdar-Shaw Professor of Molecular Pathology.
John trained initially in biochemistry at the University of Cambridge, then obtained his PhD in RNA biochemistry at the University of Leicester and studied medicine at St Bartholomew's and the Royal London School of Medicine, followed by specialty training in histopathology in Leicester, Addenbrooke's, Papworth and the Royal Brompton hospitals.
The Le Quesne laboratory use novel methods in quantitative pathology to answer questions in tumour biology, applying a range of quantitative assays to human and animal tissues. Key areas of research focus are: the inference of tumour cell phenotypes from histological images, the use of machine learning methods to extract predictive/prognostic biomarker information, and the discovery and exploitation of therapeutic targets in dysregulated mRNA translation in cancer cells.
John has said 'I am really excited to be joining ICS and the Beatson. I am highly impressed by what the city has to offer, both academically and culturally, and I can't wait to start working with the wider cancer research community here.'
You can read more about John's research here.
In a preprint available on bioRxiv (Absent expansion of pericentral hepatocytes and altered physiology in Axin2CreERT2 mice), postdoc Stephanie May and fellow researchers at the Beatson Institute reconcile discrepancies found in previous lineage tracing studies of hepatocytes. Using a CreERT2 construct knocked into the endogenous Axin2 locus, the team found no evidence of expansion of the labelled hepatocytes. They also report that this mutant allele results in profound perturbation of the Wnt pathway and physiology in the mouse.
CYRI-B inhibits actin assembly, by competing with Scar/WAVE for interaction with Rac1. In a new study (Structural Basis of CYRI-B Direct Competition with Scar/WAVE Complex for Rac1), postdoc Tamas Yelland and PhD student Anh Hoang Le reveal the nature of this interaction, presenting the crystal structures of CYRI-B and the CYRI-B:Rac1 complex. They show that CYRI-B has two subdomains: an N-terminal Rac1 binding subdomain and a C-terminal Ratchet subdomain that undergoes conformational changes induced by Rac1 binding. In a related study now available on bioRxiv (CYRI-A regulates macropinocytic cup maturation and mediates integrin uptake, limiting invasive migration), Anh Hoang Le and others at the Beatson Institute also show that CYRI-A is recruited to nascent macropinosomes (cup-like structures at the cell surface that are important for nutrient uptake and regulation of cell surface receptor levels). They show that CYRI-A enables resolution of the macropinocytic cup by suppressing actin dynamics. Furthermore, the team also reveal that CYRI-A plays an important role in internalising integrins from the cell surface.
With current clinical practice, it is not possible to identify which prostate cancer patients are at high risk of early disease recurrence following androgen deprivation therapy (ADT). Addressing this issue, Gaurav Malviya, Rachana Patel and co-authors have used human prostate cancer orthograft models to study uptake of 18F-Fluciclovine following ADT (18F-Fluciclovine mirrors the uptake of glutamine, which plays a key role in cancer metabolism). In the study (18F-Fluciclovine PET metabolic imaging reveals prostate cancer tumour heterogeneity associated with disease resistance to androgen deprivation therapy), the team find intra-tumoral heterogeneity in uptake that may explain treatment resistance. Such 18F-Fluciclovine imaging may help clinicians to identify patients at high risk of early cancer recurrence and therefore provide the opportunity to consider additional treatment.
As CRUK's Natalia Bartolome Diez put it, 'When done well, patient involvement can improve the quality and relevance of research, and is increasingly becoming a funding application requirement.' CRUK has asked researchers and people affected by cancer for their top tips on getting patient involvement right in all types and stages of research.
Here's a brief rundown of what they found:
1. Start early
The earlier you start planning patient involvement in your study, the more likely you are to involve the right people at the right time, using the most appropriate methods. Starting early helps you to gain deeper insights from the people you involve. It gives you time to embed their ideas in your research and make impactful changes as a result.
2. Take time to plan
The key to involving people affected by cancer meaningfully is planning. Taking time to think about the why, what, when and how of patient engagement will help you to identify key areas of your research that will benefit from patient involvement, and what this involvement should look like.
3. Involve the right people
You must find people affected by cancer who are able to give you the insight and information you need. Be clear about the requirements of the role and identify the skills, experience and personal attributes that the people participating in your activity will need to have.
4. Provide lay information
Explaining your study and general research topic to the people you are involving in your research will enable them to accurately feed into discussions. Information should be provided in clear, succinct, plain English. Don't assume that everyone you involve has the same abilities.
5. Establish ways of working
Ensuring that you and the people affected by cancer who become involved in your research feel comfortable and have positive experiences from the start is vital to encourage quality insight and feedback. It can be intimidating to enter a room full of researchers and muster the courage to dispute elements of their research or make suggestions. Therefore, the researchers and participants in involvement activities should agree on ways of working.
6. Don't reinvent the wheel
Make full use of the resources available from different charities, rather than trying to create a new way of doing patient involvement. CRUK can help you identify involvement opportunities at any stage of your research and support you in their delivery.
7. Always provide feedback
Many people affected by cancer start doing patient involvement because they want to 'give back' and improve outcomes for future patients with cancer. Patient involvement empowers them to influence change and provides a sense of purpose. For this reason, it is important that those involved are made aware of the impact and consequences their feedback and insight had on research.
The above is an abbreviated version of CRUK's Research Feature. Click here to read the full article.
In a pre-print available on BioRxiv ("RAL GTPases mediate EGFR/MAPK signalling-driven intestinal stem cell proliferation and tumorigenesis upstream of RAS activation"), Julia Cordero and Glasgow cancer scientists uncover a new role for Ras-like (RAL) protein in intestinal tumour growth. Beyond acting as a RAS effector, RAL stimulated the activation and internalisation of EGFR, a receptor commonly overexpressed in intestinal cancer. Hence, targeting RAL function could be an effective therapeutic approach.
Vassilis Papalazarou, Laura Machesky and colleagues describe how the Arp2/3 complex - a key factor in organising actin filaments into networks - not only has a role in the migration of melanoblasts but also in the development of skin and hair ("The Arp2/3 complex is critical for colonisation of the mouse skin by melanoblasts"). Upon depletion of the complex, melanoblasts didn't migrate properly in the developing skin, failing to populate it with hair follicles and pigment. Mechanistically, the authors suggest that melanoblasts form impaired lamellipodia and protrusions, which are essential for actin-driven migration.
Linda Rushworth, Rachana Patel, Hing Leung and colleagues identified TCEAL1 as a potential target to sensitise prostate cancer to docetaxel therapy ("In vivo CRISPR/Cas9 knockout screen: TCEAL1 silencing enhances docetaxel efficacy in prostate cancer"). Combining docetaxel treatment with TCEAL1 inhibition in culture impacted the regulation of the cell cycle and response to DNA damage. Further work is needed to investigate the effects in combination with standard care and to monitor the response in in vivo tumours.
From University of Glasgow press release (https://www.gla.ac.uk/news/headline_757602_en.html:
Dr David Bryant has been awarded £1.2m to undertake new research into colorectal carcinoma, beginning the OrgTIP project which will look at how inhibiting Phosphoinositide-modifying enzymes (PIP-MEs) could help to combat the disease. PIP-MEs are a family of genes that are commonly altered in many cancers, but particularly in bowel cancer. In bowel cancer, the PIP-MEs become uncontrolled to the extent they no longer work, or work when they shouldn't. The OrgTIP project will look at how to target the altered PIP-MEs without damaging normal cells.
Dr Bryant will also work with a biotechnology industry company partner to provide tools for the entire research community to develop new ways to combat cancer.
Dr Bryant said: "Bowel carcinoma is the 4th most common cancer in the UK, accounting for 1 out of 10 deaths from any type of cancer. While 6 out of 10 patients will respond well to current therapies, the rest will not respond to treatment. These non-responding patients have a very poor outlook and we therefore urgently need to develop new therapies to treat these patients. We hope targeting PIP-MEs may provide a new viable treatment option that may help those patients. "