Image from Dr Ezra Aksoy’s latest BCI publication makes the cover of Nature Immunology journal
Confocal imaging used in the study to show signaling by ligand-bound TLR4 transitions from plasma membrane–associated MyD88-TIRAP complexes to endosomal TRAM-TRIF complexes. Aksoy and colleagues show that the phosphatidylinositol-3-OH kinase p110delta regulates this switch by inducing dissociation of TIRAP from the membrane and degradation of TIRAP. The original confocal microscopic image by Ezra Aksoy shows PtdIns(3,4,5)P3 lipid (magenta), p110δ (yellow) and F-actin (turquoise) in mouse fibroblasts. Artwork by Lewis Long.
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Summary of the work:
Limiting immune reactions is critical for protecting the host from harm. The work by Dr Ezra Aksoy led by Professor Bart Vanhaesebroeck has revealed how p110delta (δ) isoform of the PI3K fine-tunes inflammation to avoid excessive reactions that can damage the organism. Control over the timing of Toll-like Receptor (TLR)-induced inflammation is essential and is disrupted in a range of diseases: inflammation that is triggered too quickly or not controlled appropriately can lead to a lethal endotoxic (septic) shock or, in a more chronic state, contribute to the development of diseases such as cancer, arthritis, asthma and multiple sclerosis.
A healthy immune system reacts to danger signals from their environment. The binding of microbial products or host damage-associated molecules by TLRs initiate innate immune responses and primes adaptive immunity.
The study, which was highlighted in Nature Reviews in Immunology and described in an editorial piece in Nature Immunology shows that the p110δ PI3K isoform acts as a homeostatic regulator between pro- and anti-inflammatory TLR4 signalling pathways in dendritic cells. TLR4 signalling is thought to be sequentially engaged at two distinct cell compartments. First, at the plasma membrane, LPS-bound TLR4 binds the adaptors TIRAP (Mal) and MyD88 to trigger initial signalling and induce proinflammatory cytokines. Next, in endosomes, LPS-bound TLR4 engages the adaptors TRAM and TRIF to induce the type I interferon IFN-β and the anti-inflammatory cytokine interleukin 10 (IL-10). Finally, the key finding of the new study is that after LPS stimulation, p110 δ limits TLR4-TIRAP signalling by removing the TIRAP-anchoring plasma-membrane lipid phosphatidylinositol-(4,5)-bisphosphate (PtdIns(4,5)P2) and impairing TLR4 endocytosis. This activity causes the dissociation and degradation of TIRAP. Genetic or pharmacological inactivation of p110δ prolongs plasma membrane induced signalling and the production of proinflammatory cytokines but diminishes endosomal TRAM signalling and the production of IFN-β and IL-10. The consequence of that is greater endotoxin-induced death in mice.
Given the new findings, selective and specific small-molecule inhibition of p110δ might improve vaccine efficacy or boost innate immunity in cancer, viral infection and immunodeficiency. It will be interesting to determine whether the clinical efficacy of selective inhibitors of p110δ in cancer includes proinflammatory effects.
• The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock
Ezra Aksoy, Salma Taboubi, David Torres, Sandrine Delbauve, Abderrahman Hachani, Maria A Whitehead, Wayne P Pearce, Inma Berenjeno-Martin, Gemma Nock, Alain Filloux, Rudi Beyaert, Veronique Flamand & Bart Vanhaesebroeck
• Signalling: PI3Kδ keeps TLR4 signalling on track
• Balancing pro- and anti-inflammatory TLR4 signaling
Sabine Siegemund & Karsten Sauer
BCI Honorary Clinical Lecturer contributes to landmark paper in tumour biology
Dr Marco Gerlinger, an honorary clinical lecturer at Barts Cancer Institute and a clinician scientist at Cancer Research UK is first author of a groundbreaking new paper* exploring the genetic differences within individual tumours.
Using samples taken from different parts of four separate kidney tumours, and also from sites where the cancer had spread to other organs, Dr Gerlinger and his colleagues carried out the first ever genome-wide analysis of the genetic variation between different regions of the same tumour. They found that between 63-69% of gene faults were not shared across other biopsies from the same tumour.
The findings could help explain why attempts at using single biopsies to identify biomarkers to which personalised cancer treatments can be targeted have not been more successful - but also opens the door to treatment improvements.
Dr Gerlinger explains the feat of this research;
"We tried to answer a simple but important question: Are the same genetic defects that determine tumour aggressiveness and potential treatment failure present throughout individual tumours or is there regional variation within tumours? The diversity we found in the genetic blueprints within tumours was simply astonishing. This is a major step forward to better understand cancer biology and may explain why tumours rapidly develop drug resistance and why it is so difficult to predict tumour aggressiveness from the small tumour biopsies routinely used in the clinic. We are now working towards robust methods to detect intra-tumour heterogeneity that can be used in the clinical setting and on novel drug treatment strategies which could improve patient outcomes by focusing on common genetic defects present in all cells of a tumour."
*Gerlinger M. et al, Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. New England Journal of Medicine 2012.
Cutting off the Oxygen Supply to Serious Diseases
Work by Dr Tyson Sharp and his group leads to discovery of new protein
A new family of proteins called 'LIM domain containing proteins,' which regulate the human body’s ‘hypoxic response’ to low levels of oxygen has been discovered by scientists at Barts Cancer Institute at Queen Mary, University of London and The University of Nottingham.
The researchers have uncovered a previously unknown level of hypoxic regulation at a molecular level in human cells which could provide a novel pathway for the development of new drug therapeutics to fight disease.
Cancer cells have a faulty hypoxic response which means that as the cells multiply they highjack the response to create their own rogue blood supply. In this way the cells can form large tumours. The new blood supply also helps the cancer cells spread to other parts of the body, called ‘metastasis’, which is how, ultimately, cancer kills patients.
The discovery has been published in the latest issue of the journal Nature Cell Biology. It marks a significant step towards understanding the complex processes involved in the hypoxic response which, when it malfunctions, can cause and affect the progress of many types of serious disease, including cancer.