Harnessing TNF-mediated cell death in cancer
Lead Research Organisation:
Institute of Cancer Research
Department Name: Division of Breast Cancer Research
Abstract
Inflammation and cell death are ancient processes of fundamental biological importance that enable survival and adaptation during infection and injury. Tumour necrosis factor (TNF) is the prototypical proinflammatory cytokine that signals, through its type 1 receptor (TNF-R1), either cell survival, cell proliferation or cell death1. TNF stimulates an inflammatory response whose 'purpose' is to remove the source of the disturbance, allowing the host to adapt to an abnormal condition, and, ultimately, to restore functionality and homeostasis to the tissue. However, when deregulated, inflammation can drive chronic remodelling and tissue repair, which contributes to chronic inflammatory diseases, cancer and treatment failure.
The principle idea addressed by this application is that cell survival and adaptation mechanisms of tumours are supported, at least in part, by cancer-related inflammation, and that this can be successfully targeted by switching the TNF response from pro-inflammation to cell death. Despite clear evidence that TNF can signal cell survival and death, the mechanisms that can switch between the distinct biological outcomes remain elusive. This is important as its resolution, and putative therapeutic intervention, would allow the diversion of cancer-related inflammation into activation of cell death. Our starting point for this proposal is substantial new data on the regulation of TNF-signalling and cell death.
We identified that the Ub-receptor function of cIAP1 critically controls TNF signalling, selectively regulating the pro-death effects of TNF, without inhibiting the NFkB pathway. Our preliminary data indicate that a point mutation in the Ub-binding domain of cIAP1 switches the TNF response to cell death, and completely blocks tumorigenesis. Here, we propose to use mouse models, imaging, and biochemical approaches to decipher how the Ub-receptor function of cIAP1 regulates TNF-induced cell death, and whether switching the TNF response from pro-inflammation to cell death causes tumours to permanently regress.
Cytokines of the TNF-superfamily are classic inducers of programmed necrosis (necroptosis). Although anticancer therapies that trigger the necrotic death of tumour cells may be particularly attractive to overcome apoptosis resistance, because TNF-induced necroptosis also facilitates inflammation, and deregulated inflammation can also support tumorigenesis, it will be important to carefully examine the physiological and pathological consequence of stimulating TNF-induced necrosis. At present, there is no clear evidence to indicate whether necrosis is beneficial or harmful in cancers. Here we will determine the therapeutic opportunities and pathological consequences of manipulating TNF signalling in cancer.
Given that TNF plays an eminent role in diverse pathological processes at the core of human diseases, our findings will provide new avenues for therapeutic intervention strategies.
The principle idea addressed by this application is that cell survival and adaptation mechanisms of tumours are supported, at least in part, by cancer-related inflammation, and that this can be successfully targeted by switching the TNF response from pro-inflammation to cell death. Despite clear evidence that TNF can signal cell survival and death, the mechanisms that can switch between the distinct biological outcomes remain elusive. This is important as its resolution, and putative therapeutic intervention, would allow the diversion of cancer-related inflammation into activation of cell death. Our starting point for this proposal is substantial new data on the regulation of TNF-signalling and cell death.
We identified that the Ub-receptor function of cIAP1 critically controls TNF signalling, selectively regulating the pro-death effects of TNF, without inhibiting the NFkB pathway. Our preliminary data indicate that a point mutation in the Ub-binding domain of cIAP1 switches the TNF response to cell death, and completely blocks tumorigenesis. Here, we propose to use mouse models, imaging, and biochemical approaches to decipher how the Ub-receptor function of cIAP1 regulates TNF-induced cell death, and whether switching the TNF response from pro-inflammation to cell death causes tumours to permanently regress.
Cytokines of the TNF-superfamily are classic inducers of programmed necrosis (necroptosis). Although anticancer therapies that trigger the necrotic death of tumour cells may be particularly attractive to overcome apoptosis resistance, because TNF-induced necroptosis also facilitates inflammation, and deregulated inflammation can also support tumorigenesis, it will be important to carefully examine the physiological and pathological consequence of stimulating TNF-induced necrosis. At present, there is no clear evidence to indicate whether necrosis is beneficial or harmful in cancers. Here we will determine the therapeutic opportunities and pathological consequences of manipulating TNF signalling in cancer.
Given that TNF plays an eminent role in diverse pathological processes at the core of human diseases, our findings will provide new avenues for therapeutic intervention strategies.
Technical Summary
Deregulated cell death and inflammation can drive chronic remodelling and tissue repair, which can contribute to cancer and treatment failure. The principle idea addressed by this application is that cell survival and adaptation mechanisms of tumours are supported, at least in part, by cancer-related inflammation, and that this can be successfully targeted by switching the TNF response from pro-inflammation to activation of cell death, causing tumours to permanently regress.
Despite clear evidence that TNF can signal cell survival and death, the mechanisms that can switch between the distinct biological outcomes remain elusive. This is important as its resolution, and putative therapeutic intervention, would allow the diversion of cancer-related inflammation into activation of cell death. Our starting point for this proposal is substantial new data on the regulation of TNF-signalling and cell death.
We identified that the Ub-receptor function of cIAP1 critically controls TNF signalling, selectively regulating the pro-death effects of TNF, without inhibiting the NFkB pathway. Our preliminary data indicate that a point mutation in the Ub-binding domain of cIAP1, which abrogates its ability to bind to M1- and K63-linked Ub chains, switches the TNF response to cell death, and completely blocks tumorigenesis. Mechanistically, we find that the Ub-binding domain of cIAP1 regulates intracellular trafficking of TNF-R1, and the consequences of RIPK1 ubiquitylation. Our data are consistent with a scenario whereby Ub-binding of cIAP1 participates with ESCRT-0 in capturing and sorting ubiquitylated TNF-R1 and RIPK1 for recycling.
Here, we propose to use mouse models, imaging, and biochemical approaches to decipher how the Ub-receptor function of cIAP1 regulates TNF-induced cell death, and whether switching the TNF response from pro-inflammation to cell death is beneficial or harmful in cancer.
Despite clear evidence that TNF can signal cell survival and death, the mechanisms that can switch between the distinct biological outcomes remain elusive. This is important as its resolution, and putative therapeutic intervention, would allow the diversion of cancer-related inflammation into activation of cell death. Our starting point for this proposal is substantial new data on the regulation of TNF-signalling and cell death.
We identified that the Ub-receptor function of cIAP1 critically controls TNF signalling, selectively regulating the pro-death effects of TNF, without inhibiting the NFkB pathway. Our preliminary data indicate that a point mutation in the Ub-binding domain of cIAP1, which abrogates its ability to bind to M1- and K63-linked Ub chains, switches the TNF response to cell death, and completely blocks tumorigenesis. Mechanistically, we find that the Ub-binding domain of cIAP1 regulates intracellular trafficking of TNF-R1, and the consequences of RIPK1 ubiquitylation. Our data are consistent with a scenario whereby Ub-binding of cIAP1 participates with ESCRT-0 in capturing and sorting ubiquitylated TNF-R1 and RIPK1 for recycling.
Here, we propose to use mouse models, imaging, and biochemical approaches to decipher how the Ub-receptor function of cIAP1 regulates TNF-induced cell death, and whether switching the TNF response from pro-inflammation to cell death is beneficial or harmful in cancer.
Planned Impact
Impact and potential beneficiaries of this research:
-Scientific community:
The successful conclusion of the proposed project is expected to provide a better understanding of the molecular mechanisms that control Ubiquitin (Ub)-dependent regulation of signal transduction pathways that influence the ability of multi-cellular organisms to adapt to perturbations. As such our research addresses fundamental issues relevant to normal animal physiology and following exposure to stress. Further, as Ub-mediated regulation of cell death and tissue repair is involved in almost every aspect of life, the proposed project will also impact the health-care community. Of particular interest is the notion that cell death regulatory proteins also fulfill nonlethal functions in differentiation and tissue remodeling. It is now clear that the cell death machinery is involved in releasing signals to communicate with their cellular environment, to promote cell division, tissue regeneration, and wound healing. Unraveling the molecular details governing this process could lead to a better understanding of aging, tissue regeneration and cancer.
- Cancer patients:
One of the key problems in cancer is the adaptive nature of tumours. It is now recognised that the Ub system modulates key signal transduction pathways that have direct implications in the 'evolvability' of tumours. Hence, cancer treatments would be significantly more successful if it was possible to target Ub-dependent signalling events. Our research addresses a fundamental aspect of Ub-dependent tissue repair. Ultimately, this work will provide new insights into the mechanisms through which Ub-dependent signalling contributes to cancer, and how we can translate this information for patient benefit.
- Public sector, Academia/Pharma based drug development teams:
Given TNF's importance under physiological and pathological conditions, and its central role in chronic inflammatory diseases, inflammation-associated cancer, and cancer-related inflammation, the results of this project will be of significant interest not only for academic but also private drug development groups. The identification of the molecular mechanisms through which TNF signalling can be switched from pro-inflammation to cell death will open up new avenues for therapeutic intervention strategies. It is anticipated that a clinical trial could follow from this study within five years. This will have obvious benefits in health and well being affecting the public sector, and can be exploited by the industry for the development of novel technologies for prevention and therapy of liver cancer in the early phases of the disease.
- General public, schools:
The project is a clear-cut example of the development of suitable experimental models for understanding the mechanism of disease and to develop new methods for prevention and cure. Thus results arising from the project can be used to illustrate the process in education, leading to obvious cultural benefits by emphasizing the importance of scientific approaches in health care.
-Scientific community:
The successful conclusion of the proposed project is expected to provide a better understanding of the molecular mechanisms that control Ubiquitin (Ub)-dependent regulation of signal transduction pathways that influence the ability of multi-cellular organisms to adapt to perturbations. As such our research addresses fundamental issues relevant to normal animal physiology and following exposure to stress. Further, as Ub-mediated regulation of cell death and tissue repair is involved in almost every aspect of life, the proposed project will also impact the health-care community. Of particular interest is the notion that cell death regulatory proteins also fulfill nonlethal functions in differentiation and tissue remodeling. It is now clear that the cell death machinery is involved in releasing signals to communicate with their cellular environment, to promote cell division, tissue regeneration, and wound healing. Unraveling the molecular details governing this process could lead to a better understanding of aging, tissue regeneration and cancer.
- Cancer patients:
One of the key problems in cancer is the adaptive nature of tumours. It is now recognised that the Ub system modulates key signal transduction pathways that have direct implications in the 'evolvability' of tumours. Hence, cancer treatments would be significantly more successful if it was possible to target Ub-dependent signalling events. Our research addresses a fundamental aspect of Ub-dependent tissue repair. Ultimately, this work will provide new insights into the mechanisms through which Ub-dependent signalling contributes to cancer, and how we can translate this information for patient benefit.
- Public sector, Academia/Pharma based drug development teams:
Given TNF's importance under physiological and pathological conditions, and its central role in chronic inflammatory diseases, inflammation-associated cancer, and cancer-related inflammation, the results of this project will be of significant interest not only for academic but also private drug development groups. The identification of the molecular mechanisms through which TNF signalling can be switched from pro-inflammation to cell death will open up new avenues for therapeutic intervention strategies. It is anticipated that a clinical trial could follow from this study within five years. This will have obvious benefits in health and well being affecting the public sector, and can be exploited by the industry for the development of novel technologies for prevention and therapy of liver cancer in the early phases of the disease.
- General public, schools:
The project is a clear-cut example of the development of suitable experimental models for understanding the mechanism of disease and to develop new methods for prevention and cure. Thus results arising from the project can be used to illustrate the process in education, leading to obvious cultural benefits by emphasizing the importance of scientific approaches in health care.
Organisations
- Institute of Cancer Research (Lead Research Organisation)
- ETH Zurich (Collaboration)
- Klinikum der Universität München (Collaboration)
- University of Basel (Collaboration)
- University of Michigan (Collaboration)
- University College Dublin (Collaboration)
- University of Innsbruck (Collaboration)
- Kiel University (Collaboration)
- Max Planck Society (Collaboration)
- University of Ghent (Collaboration)
- The Walter and Eliza Hall Institute of Medical Research (WEHI) (Collaboration)
- Albert Ludwig University of Freiburg (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- Medical Research Council (MRC) (Collaboration)
- Columbia University (Collaboration)
- Francis Crick Institute (Collaboration)
- Canadian Institutes of Health Research (Collaboration)
- University of Lausanne (Collaboration)
- HARVARD UNIVERSITY (Collaboration)
- University College London (Collaboration)
- Astex Pharmaceuticals (Collaboration)
- Genentech, Inc (Collaboration)
- Technical University of Denmark (Collaboration)
- Auburn University (Collaboration)
- University of Cologne (Collaboration)
- Institute of Cancer Research UK (Collaboration)
Publications
Annibaldi A
(2018)
Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.
in Molecular cell
Annibaldi A
(2018)
Checkpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer.
in Trends in molecular medicine
Annibaldi A
(2018)
Ripk1 and haematopoiesis: a case for LUBAC and Ripk3.
in Cell death and differentiation
Banreti AR
(2020)
The NMDA receptor regulates competition of epithelial cells in the Drosophila wing.
in Nature communications
Brasó-Maristany F
(2016)
PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer
in Nature Medicine
Ciuffa R
(2022)
Novel biochemical, structural, and systems insights into inflammatory signaling revealed by contextual interaction proteomics.
in Proceedings of the National Academy of Sciences of the United States of America
Feltham R
(2018)
Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1's Cytotoxic Potential
in Cell Reports
Feoktistova M
(2016)
Techniques to Distinguish Apoptosis from Necroptosis.
in Cold Spring Harbor protocols
Galluzzi L
(2018)
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.
in Cell death and differentiation
Galluzzi L
(2015)
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015.
in Cell death and differentiation
Description | Harnessing cell death mechanisms to overcome treatment resistance and improve tumour immunity |
Amount | £1,248,841 (GBP) |
Funding ID | 24399 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2018 |
End | 01/2024 |
Title | CRISPR knockout cells |
Description | We have generated various cell lines that lack individual components of the TNF receptor signalling complex |
Type Of Material | Biological samples |
Year Produced | 2015 |
Provided To Others? | Yes |
Impact | The generation of specific knockout cell lines will help the dissection of inflammation and cell death in cancer. |
Title | CRISPR mediated deletion of specific DNA regions |
Description | we developed improved techniques to apply the CRISPR/CAS9 technique to delete specific genes from the genome |
Type Of Material | Technology assay or reagent |
Year Produced | 2015 |
Provided To Others? | No |
Impact | This will improve the way through which we analyse the function of specific genes. |
Title | Detection of Ripoptosome assembly |
Description | Here we have developed a proximity ligation assay to detect the assembly of the ripoptosome, a large (2kDa) protein complex consisting of RIPK1, FADD, Caspase-8, FLIP, RIPK3 and Myo7a. We use a combination of antibodies that generate a localized, discrete signal only when two proteins are in close proximity, that is, in a complex. Using specific primary antibodies against the respective members of the complex, which in turn are recognized by oligonucleotide-coupled secondary antibodies, we can obtaine discrete proximity labelling of protein:protein interactions, confirming their close proximity. To control for nonspecific binding between the various secondary antibodies, we generally add only one or no primary antibody to the reaction. This results in no signal. We find that MYO7A/CASP8 proximity labelling is entirely dependent on the presence of RIPK1. Accordingly, depletion of Ripk1 by RNAi completely abolishes CASP8/MYO7A proximity signals. Likewise, the interaction between CASP8 and RIPK3 is strictly RIPK1 dependent. This result also demonstrates that the observed proximity signal is not due to nonspecific binding of the primary antibodies. The requirement of RIPK1 for the generation of CASP8/MYO7A or CASP8/RIPK3 proximity signals strongly suggests that CASP8 and MYO7A or CASP8 and RIPK3 interact with one another within RIPK1- based protein complexes such as the ripoptosome. |
Type Of Material | Technology assay or reagent |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | This method allows single cell analysis of protein complexes in situ, that is without breaking up cells. |
Title | IAP research reagents |
Description | we have generated various cell lines that harbour specific mutations in the cIAP gene |
Type Of Material | Cell line |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | This allows the dissection of inflammation and cell death, and provide important insights for future anti-cancer therapies. |
Title | Organoid tumour models |
Description | We have created various tumour organoid lines that we can use to study immunogenic cell death in C57BL/6 mice. |
Type Of Material | Cell line |
Year Produced | 2021 |
Provided To Others? | No |
Impact | not available yet. But this reagent will allow us to create patient cohorts for the development of novel treatment protocols. |
Title | Phosphorylation-specific antibody for RIPK1 S320/321 |
Description | This phosphorus-specific antibody detects phosphorylation of RIPK1 at position S321 of mouse and S320 of human RIPK1 |
Type Of Material | Antibody |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | This antibody is being used by many labs to study MK2-mediated phosphorylation of RIPK1 |
Title | Prescission mediated characterisation of Ubiquitin linkages on specific lysine residues |
Description | We developed a new method that allows the characterisation of specific Ubiquitin linkage types on specific lysine residues. This is important because specific Ubiquitin linkages emanate specific signalling events. However, so far it has been impossible to characterise this. This is the first time that it will be possible to map the linkage types on specific lysine residues. |
Type Of Material | Technology assay or reagent |
Provided To Others? | No |
Impact | This represents a paradigm shift in the way Ub signalling will be analysed. This method will help to characterise specific signalling events in vivo. |
Title | TRIF- and ZBP1-deficient KO cell lines |
Description | To study the role of TRIF and ZBP1 we created double deficient KO lines in L929, E0771, HT29 and HaCaT cells. |
Type Of Material | Cell line |
Year Produced | 2021 |
Provided To Others? | No |
Impact | not available yet. |
Title | TRIF-deficient KO cell lines |
Description | To study the role of TRIF in health and disease we have created TRIF mutant knockout lines in L929, E0771, HT29 and HaCaT cells. |
Type Of Material | Cell line |
Year Produced | 2021 |
Provided To Others? | No |
Impact | not available yet. |
Title | Ubiquitin restriction analysis |
Description | We have improve the UbiCrest technique that allows the characterisation of Ubiquitin-dependent signalling events |
Type Of Material | Technology assay or reagent |
Year Produced | 2015 |
Provided To Others? | Yes |
Impact | This will allow to dissect the signalling events that control inflammation and cancer development |
Title | ZBP1 mutant cell lines |
Description | we have created reconstituted ZBP1 cell lines in which endogenous ZBP1 was replaced with various mutant versions. |
Type Of Material | Technology assay or reagent |
Year Produced | 2021 |
Provided To Others? | No |
Impact | not available yet |
Title | ZBP1-deficient KO cell lines |
Description | To study the role of ZBP1 in nucleic acid sensing we generated ZBP1-KO CRISPR lines in L929, E0771, HT29 and HaCaT cell lines. |
Type Of Material | Cell line |
Year Produced | 2021 |
Provided To Others? | No |
Impact | not available yet |
Title | cIAP1 UBA knockin mouse |
Description | To study the function of the UBA domain of cIAP1 in vivo, we generated a conditional knock-in mouse bearing the MF>AA mutation in the absence of cIAP2. Previous work indicated that cIAP1 and cIAP2 function redundantly to each other. Therefore, we generated the conditional cIAP1UBAmut mouse from an ES cell clone that previously had been targeted at the cIAP2 locus. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | While it is beyond doubt that cIAPs suppress TNF-induced cell death, how this is achieved remains unclear. The main problem in dissecting cIAP-mediated regulation of TNF-induced cell death has been the fact that the signaling aspect of Ub (recruitment/ activation of TAK1, IKK, MK2, and NF-kB-mediated gene induction) and the direct Ub-dependent anti-apoptotic function of cIAPs cannot be separated. We now identified a point mutation in cIAP1 that selectively sensitizes cells to TNFinduced cell death, without interfering with TNF-mediated activation of NF-kB, and IKK- and MK2-mediated phosphorylation of RIPK1. This mutation affects the evolutionarily conserved ubiquitin-associated (UBA) domain of cIAP1. Mice with a knockin mutation in the UBA domain develop normally but are acutely sensitive to TNF-induced systemic inflammatory response syndrome (SIRS), which is caused by enhanced sensitivity to TNF-mediated cell death. Our data are consistent with the notion that the UBA domain is required for Ub-mediated regulation of RIPK1 kinase activity. |
Title | primary and immortalised murine cell lines |
Description | Using wild-type and mutant mouse strains, we generated different primary and immortalised mouse lines. These included mouse embryonic fibroblasts, mouse dermal fibroblasts, bone marrow derived macrophages and keratinocytes. Such cells were generated from the following mouse strains: WT, cIAP1-/-, cIAP2-/-, cIAP1cIAP2-DKO (double knockout), Ripk1-/-, Ripk3-/-, Mlkl-/-, cascade-8-/-, Ripk1casp8-DKO, cIAP1-UBAcIAP2-/-, cIAP1-UBA. |
Type Of Material | Cell line |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | Many of these reagents were requested by other research labs, and form the basis of future investigations. |
Description | Development of a RIPK1-PROTAC small molecule |
Organisation | Institute of Cancer Research UK |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | To develop a small pharmacological compound that is capable of degrading the protein RIPK1, we set up a collaboration with Swen Hoelder and Ben Bellenie. We are providing the biological assay systems in which to test the ability of the synthesised degraders to deplete RIPK1. |
Collaborator Contribution | The team around Swen Hoelder is synthesising new compounds, evaluate PKs and other pharmacological evaluations of the newly synthesised drugs. |
Impact | not available yet |
Start Year | 2022 |
Description | FDA approved inhibitors of RIPK1 |
Organisation | University of Kiel |
Country | Germany |
Sector | Academic/University |
PI Contribution | In collaboration with Stefan Krautwald at the University of Kiel we are attempting to identify FDA approved drugs to evaluate their inhibitory capacity of RIPK1, a central regulator of inflammatory based diseases. We are providing Stefan Krautwald with reagents and know how. |
Collaborator Contribution | Stefan Krautwald at the University of Kiel is characterising FDA approved drugs to repurpose readily available drugs for the treatment of chronic inflammatory diseases and other pathologies, including those triggered by SARS-CoV2. |
Impact | This work was published in CDD. |
Start Year | 2019 |
Description | Harnessing cell death mechanisms to improve therapeutic responses in lung cancer |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We conducted several experiments to test what therapeutic combinations would be best suited to kill a particular lung cancer type |
Collaborator Contribution | Our collaborators provided an in vivo mouse model for lung cancer in which we could test the therapeutic benefit of a particular drug combination. |
Impact | Our experiment contributed to the finding that targeting LUBAC sensitises lung cancer cells to chemotherapy. This work was published in J. Exp Med doi: 10.1084/jem.20180742 |
Start Year | 2016 |
Description | IAP-mediated regulation of SIRS |
Organisation | University of Ghent |
Department | Department of Biomedical Molecular Biology |
Country | Belgium |
Sector | Academic/University |
PI Contribution | We have generated double targets KO/KI animals of cIAP2/cIAP1 to test the role of the ubiquitin-binding domain of cIAP1. We find that cells from such animals are sensitive cytokine induced cell death. |
Collaborator Contribution | Our collaborator have tested the in vivo sensitivity of such animals using a model for Systemic Inflammatory Response Syndrome (SIRS). |
Impact | not available yet |
Start Year | 2016 |
Description | Identification of specific Ubiquitin chains on components of the TNF receptor signalling complex |
Organisation | Medical Research Council (MRC) |
Department | MRC Laboratory of Molecular Biology (LMB) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | we have provide novel findings to address the question what types of signalling chains are conjugated to specific components of the TNF receptor signalling complex. |
Collaborator Contribution | The collaborator has provided us with recombinant enzymes that allowed us to investigate the Ubiquitin linkage types that are conjugated to components of the TNF receptor signalling complex. |
Impact | the study that reports the findings from this collaboration has been accepted for publication at Molecular Cell. This study has led to a better understanding of TNF signalling |
Start Year | 2015 |
Description | Immunogenic Cell Death |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Different types of cell deaths have different immunological consequences. Here we are collaborate with scientists at the CRICK to learn the latest methodologies in measuring cross priming of CD8+ T cells. |
Collaborator Contribution | The scientists at the CRICK are teaching us methods of measuring cross priming of CD8+ T cells. |
Impact | no outputs have yet occurred |
Start Year | 2018 |
Description | Immunogenic Cell Death-2 |
Organisation | Genentech, Inc |
Country | United States |
Sector | Private |
PI Contribution | We are collaborating with Genentech in identifying cell death mechanics that are most immunogenic, meaning that they activate a patient's own immune system. |
Collaborator Contribution | Our collaborators are sharing with us reagents and methodologies that help us to characterise immunogenic cell death. |
Impact | no outputs have yet arisen. |
Start Year | 2019 |
Description | MIB-mediated regulation of CYLD |
Organisation | University College London |
Department | MRC Laboratory for Molecular Cell Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We identify that the E3 ligase MIB2 targets the deubiquitylase CYLD for ubiquitylation and inactivation, providing a new concept through which DUBs can be regulated. |
Collaborator Contribution | Our collaborators structurally investigated how ubiquitylation of CYLD might influence its activity. |
Impact | This collaboration resulted in the identification of a novel concept of DUB regulation. The collaboration ended with MRC because the collaborator left for the Walter and Eliza Hall in Melbourne, Australia. |
Start Year | 2016 |
Description | MIB-mediated regulation of inflammation |
Organisation | University College Dublin |
Department | School of Medicine and Medical Science |
Country | Ireland |
Sector | Academic/University |
PI Contribution | We provided reagents and cell lines to investigate the role of Mind bomb E3 ligases in cytokine signalling. This provided the Martin lab with important reagents, and will provide them with co-authorship on a publication, which is currently submitted to Molecular Cell |
Collaborator Contribution | This collaboration allowed us to investigate the role of Mind bomb E3 ligases in the regulation of TNF-mediated induction of cytokines. Seamus Martin from Trinity College conducted cytokine profiles and TNF dose response curves for us. |
Impact | the publication that reports this collaboration is currently under review in Molecular Cell. The work established that Mind Bomb E3 ligases play no role in TNF-mediated activation of cytokines in a panel of cell lines. The observation contributes to our current understanding of inflammatory signalling and how cross-priming can be achieved, thereby improving anti-cancer strategies. |
Start Year | 2015 |
Description | MIB2-mediated regulation of RIPK1 and CYLD |
Organisation | Harvard University |
Department | Department of Biological Chemistry & Molecular Pharmacology (BCMP) |
Country | United States |
Sector | Academic/University |
PI Contribution | We identified a novel mechanism through which MIB E3 ligases regulate RIPK1-mediated cell death. This identified the Dead Domain of RIPK1 as an acceptor domain for Ubiquitin. |
Collaborator Contribution | Hao Wu modelled the Death Domain of RIPK1 to investigate whether the ubiquitylation of this domain might interfere with its function. |
Impact | This collaboration resulted in an improved understanding of RIPK1 signalling.. |
Start Year | 2016 |
Description | MK2-mediated regulation of RIPK1 |
Organisation | The Walter and Eliza Hall Institute of Medical Research (WEHI) |
Department | Cell Signalling and Cell Death Division |
Country | Australia |
Sector | Charity/Non Profit |
PI Contribution | We provided our collaborators with vital information with regards to how the MK2 kinase regulates RIPK1. We further provided them with experiment, which demonstrated that MK2 directly regulates cell death by phosphorylating RIPK1 in health and disease. |
Collaborator Contribution | Our collaborators provided us with AML tumour models to test whether inhibition of MK2 might provide a therapeutic benefit in combination with IAP inhibitors. |
Impact | this collaboration resulted in improved understanding of how MK2 contributes to tumour formation and treatment failure. The collaboration also resulted in a submission of a manuscript to Mol Cell. |
Start Year | 2016 |
Description | MK2-mediated regulation of cell death |
Organisation | Klinikum der Universität München |
Country | Germany |
Sector | Academic/University |
PI Contribution | this collaboration focuses on the complex relationship between cell death and inflammation. In particular we have been investigating how MK2 regulates RIP kinase activity. We identified that MK2 directly phosphorylates RIPK1 at residue S321, a site previously been identified by Manolis Pasparakis (University of Cologne) and John Silke (WEHI). We established this collaboration to establish how MK2 regulates RIPK1 in health and disease. Our collaborators provided us with biological materials from the knock-in animals, which we analysed for their sensitivity to death triggers |
Collaborator Contribution | Our collaborators generated a knock-in mouse that bears phospho-mimicking and non-phosphorylatable mutants of RIPK1. Moreover, our collaborator provided patient samples that we analysed. |
Impact | Generation of genetically engineered animals, and cells thereof. |
Start Year | 2016 |
Description | MK2-mediated regulation of cell death |
Organisation | The Walter and Eliza Hall Institute of Medical Research (WEHI) |
Country | Australia |
Sector | Academic/University |
PI Contribution | this collaboration focuses on the complex relationship between cell death and inflammation. In particular we have been investigating how MK2 regulates RIP kinase activity. We identified that MK2 directly phosphorylates RIPK1 at residue S321, a site previously been identified by Manolis Pasparakis (University of Cologne) and John Silke (WEHI). We established this collaboration to establish how MK2 regulates RIPK1 in health and disease. Our collaborators provided us with biological materials from the knock-in animals, which we analysed for their sensitivity to death triggers |
Collaborator Contribution | Our collaborators generated a knock-in mouse that bears phospho-mimicking and non-phosphorylatable mutants of RIPK1. Moreover, our collaborator provided patient samples that we analysed. |
Impact | Generation of genetically engineered animals, and cells thereof. |
Start Year | 2016 |
Description | MK2-mediated regulation of cell death |
Organisation | University of Cologne |
Department | The Institute for Genetics |
Country | Germany |
Sector | Academic/University |
PI Contribution | this collaboration focuses on the complex relationship between cell death and inflammation. In particular we have been investigating how MK2 regulates RIP kinase activity. We identified that MK2 directly phosphorylates RIPK1 at residue S321, a site previously been identified by Manolis Pasparakis (University of Cologne) and John Silke (WEHI). We established this collaboration to establish how MK2 regulates RIPK1 in health and disease. Our collaborators provided us with biological materials from the knock-in animals, which we analysed for their sensitivity to death triggers |
Collaborator Contribution | Our collaborators generated a knock-in mouse that bears phospho-mimicking and non-phosphorylatable mutants of RIPK1. Moreover, our collaborator provided patient samples that we analysed. |
Impact | Generation of genetically engineered animals, and cells thereof. |
Start Year | 2016 |
Description | MLKL-mediated Necroptosis |
Organisation | Auburn University |
Country | United States |
Sector | Academic/University |
PI Contribution | This collaboration focusses on the regulation of necroptosis, a controlled form of lytic cell death. We have identified a regulatory mechanism through which the key effector MLKL triggers necroptosis. In particular we have generated a MLKL knock-in mouse model in which we changed a particular residue that is important for MLKL regulation. We have done all the preliminary characterisation of this model with respect to its sensitivity to cel death induction. |
Collaborator Contribution | Jason Upton, a world leader in virus induced necroptosis, at Auburn University tested the in vivo relevance of the MLKL mutation. He assessed whether the mutant animal, and cells thereof, is more susceptible to viral infection. |
Impact | This collaboration is multi-disciplinary. Discipline involved are: cell death immunity inflammation virology |
Start Year | 2019 |
Description | RIPK1-mediated regulation of immunogenic cell death |
Organisation | Auburn University |
Country | United States |
Sector | Academic/University |
PI Contribution | Here we are testing the role of RIPK1 in regulating immunogenic cell death. We have developed a pharmacological PROTAC compound that targets RIPK1 for degradation. This enables us to evaluate the role of RIPK1 in controlling intracellular signalling events that control the immunogenicity of cell death events. |
Collaborator Contribution | To study the role of RIPK1 in regulating TNFR1, TLR3 and ZBP1-mediated necroptosis (a lytic form of cell death), we have collaborated with Manolis Pasparakis who is providing us with bone marrow from various knockout animals. We are also collaborating with Jason Upson who is an expert in ZBP1-mediated necroptosis. Jason is in the possession of various viruses that can be used to trigger ZBP1-induced necroptosis. With the help of our RIPK1-PROTAC it will be possible to evaluate the role of RIPK1 in this process. |
Impact | These experiments will provide us with a deep understanding of the signalling processes that regulate the immunogenicity of cell death. |
Start Year | 2021 |
Description | RIPK1-mediated regulation of immunogenic cell death |
Organisation | University of Cologne |
Department | CECAD Research Center |
Country | Germany |
Sector | Academic/University |
PI Contribution | Here we are testing the role of RIPK1 in regulating immunogenic cell death. We have developed a pharmacological PROTAC compound that targets RIPK1 for degradation. This enables us to evaluate the role of RIPK1 in controlling intracellular signalling events that control the immunogenicity of cell death events. |
Collaborator Contribution | To study the role of RIPK1 in regulating TNFR1, TLR3 and ZBP1-mediated necroptosis (a lytic form of cell death), we have collaborated with Manolis Pasparakis who is providing us with bone marrow from various knockout animals. We are also collaborating with Jason Upson who is an expert in ZBP1-mediated necroptosis. Jason is in the possession of various viruses that can be used to trigger ZBP1-induced necroptosis. With the help of our RIPK1-PROTAC it will be possible to evaluate the role of RIPK1 in this process. |
Impact | These experiments will provide us with a deep understanding of the signalling processes that regulate the immunogenicity of cell death. |
Start Year | 2021 |
Description | Regulation of RIPK1 kinase activation |
Organisation | University of Innsbruck |
Country | Austria |
Sector | Academic/University |
PI Contribution | In collaboration with the University of Innsbruck we are evaluating the mechanism of activation of the RIPK1 kinase. We are generating various constructs that are used by our collaborators to evaluate conformational changes. We are providing expertise in RIPK1 signalling. |
Collaborator Contribution | In collaboration with the University of Innsbruck we are evaluating the mechanism of activation of the RIPK1 kinase. We are generating various constructs that are used by our collaborators to evaluate conformational changes. |
Impact | not yet available |
Start Year | 2019 |
Description | Regulation of TNF signalling |
Organisation | ETH Zurich |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | Here we worked with the Aebersold lab to characterise the interactome of the TNF-receptor-I signalling complex. We trained members of the Aebersold lab to purify TNF-receptor signalling complex-I and -II from cells. Moreover, we helped with advise and prioritisation of leads. |
Collaborator Contribution | The Aebersold lab identified the composition, stoichiometry, temporal organization and cellular requirements for the formation of the TNF-receptor signaling complex (TNF-RSC). Overall, they showed that the integration of systems- and structure-level information provides a generic, largely unexplored link between the modular proteome and cellular function. |
Impact | The above mentioned approach resulted in the identification of 2 new components of the TNF-RSC, namely WRNIP1 and UBASH3b. Moreover, it produced large amount of interaction data, highlighting the complexity of the TNF signalling. This project was only possible due to its multi-disciplinary nature. Disciplines: Mass spectrometry Cellular Biology |
Start Year | 2021 |
Description | Regulation of TNF signalling by WRNIP1 |
Organisation | The Walter and Eliza Hall Institute of Medical Research (WEHI) |
Country | Australia |
Sector | Academic/University |
PI Contribution | We have generated WRNIP1-knockout analysis that we are currently characterising. Detailed mass spectrometric analysis identified WRNIP1 as component of the TNF-receptor Signalling Complex. We now would like to test whether such animals exhibit defects in TNF signalling. To maximise our efforts we have joined up with John Silke at the WEHI to study these animals. In particular, Prof Silke will be testing whether cpdm mice are more sensitive to skin inflammation when WRNIP1 is lost. |
Collaborator Contribution | Prof. John Silke is helping out with the analysis of WRNIP-KO animals. In particular, he is evaluating whether these animals exhibit defects in TNF signalling and TNF-induced cell death. |
Impact | These experiments are designed to provide a better understanding of TNF signalling in health and disease. |
Start Year | 2020 |
Description | Regulation of cell competition |
Organisation | Columbia University |
Department | Department of Genetics and Development |
Country | United States |
Sector | Academic/University |
PI Contribution | We have provide a novel molecular link in the regulation of cell competition and inflammatory signalling. In addition, we have provided reagents and research tools to our collaborator. |
Collaborator Contribution | Our collaborator investigated the involvement of our key protein in their assay system to gain a better understand of the regulatory mechanisms of cell competition. |
Impact | currently there are no outputs or outcomes of this collaboration |
Start Year | 2015 |
Description | Regulation of necroptosis |
Organisation | The Walter and Eliza Hall Institute of Medical Research (WEHI) |
Country | Australia |
Sector | Academic/University |
PI Contribution | Here we are studying the molecular mechanism through which the necroptosis effector MLKL is activated and how its cytotoxic potential is regulated. The key aspect is to understand how we can induce necroptosis in cancer cells. Necroptosis is an immunogenic form of cell death that will greatly help to activate a patient's own immune system against cancer. |
Collaborator Contribution | James Murphy is providing structural support and advise in studying MLKL, a key effector of necroptosis. James previously crystallised MLKL (Immunity. 2013 Sep 19;39(3):443-53; Biochem J. 2013 Nov 13), which has greatly helped us in resolving how MLKL is regulated. |
Impact | not applicable yet. |
Start Year | 2019 |
Description | Regulation of the pseudokinase MLKL |
Organisation | The Walter and Eliza Hall Institute of Medical Research (WEHI) |
Country | Australia |
Sector | Academic/University |
PI Contribution | We are assessing the molecular mechanism of MLKL-mediated necroptosis and how this potentially catastrophic event is controlled. |
Collaborator Contribution | James Murphey is providing us with reagents and insights into the molecular workings of MLKL. |
Impact | not yet available |
Start Year | 2019 |
Description | Saint Analysis of putative binding partners of components of the TNF receptor signalling complex |
Organisation | University of Michigan |
Country | United States |
Sector | Academic/University |
PI Contribution | We provided extensive mass spec data sets for analysis. |
Collaborator Contribution | The collaborators used the provided mass spec data set to run Saint Algorithms. This identified putative binding partners of components of the TNF receptor signalling complex. |
Impact | the data reporting this analysis has been accepted at Cell Reports. |
Start Year | 2014 |
Description | Targeting IAPs in cancer |
Organisation | Astex Pharmaceuticals |
Department | Astex Therapeutics Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | We are testing whether combining ASTX660 with immune checkpoint inhibitors is beneficial to restrain tumour growth. To this end we are using immune competent C57BL/6 mice. We are testing these combinations in a model of lung and breast cancer. |
Collaborator Contribution | Together with ASTEX we are exploring the clinical benefit of combining the IAP antagonist ASTX660 with immune checkpoint inhibitors in patients with cancer. ASTEX is providing us with the ASTX660 compound |
Impact | outputs are not yet available |
Start Year | 2019 |
Description | The role of IAPs and cytokine signalling in pancreatic cancer |
Organisation | University of Lausanne |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | We have generated double targeted KO (lacking cIAP1 and cIAP2) animals that we are currently characterising for their phenotype with regards to cell death, inflammation and cancer. We have identified that these animals are sensitised to cytokine induced cell death. |
Collaborator Contribution | Our collaborator will investigate whether conditional animals with targeted alleles in cIAP1 and cIAP2 are resistant to inflammation driven pancreatitis. |
Impact | not yet available |
Start Year | 2016 |
Description | UBA mediated regulation of Th17 helper cells |
Organisation | Technical University of Denmark |
Department | Department of Micro and Nanotechnology |
Country | Denmark |
Sector | Academic/University |
PI Contribution | Our collaborators investigated the role of the UBA domain in cIAP1 for the development and functionality of Th17 T helper cells. They examined bones from animals harbouring a point mutation in the Ubiquitin-associated domain of cIAP1 to test whether this domain affects the population of T-helper cells of the Th17 subtype |
Collaborator Contribution | We generated Knockin animals harbouring a point mutation in the UBA domain of cIAP1, and provided such animals to our collaborator |
Impact | Detailed analysis revealed that the UBA domain of cIAP1 does not affect Th17 cell function. |
Start Year | 2017 |
Description | UbiCrest analysis of cytokine signalling |
Organisation | Medical Research Council (MRC) |
Department | MRC Laboratory of Molecular Biology (LMB) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Using the UbiCrest methodology, we are studying the ubiquitin linkage types that are mediated by IAPs. This provides us with a conceptional framework how inflammatory signalling is achieved and regulated. |
Collaborator Contribution | David Komander has provided us with the necessary reagents to conduct the UbiCrest analysis. |
Impact | Using the UbiCrest analysis tool set we determined the linkage repertoire on components of the TNF signalling complex. This has resulted in a better understanding of TNF signalling in health and disease. |
Start Year | 2015 |
Description | Ubiquitin-mediated regulation of RIPK1 kinase activity |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | We are investigating the mechanism of RIPK1 kinase regulation and have developed a unique model system to study how ubiquitylation of RIPK1 controls its kinase activity |
Collaborator Contribution | GSK has provided us with RIPK1 kinase inhibitors. |
Impact | This collaboration has led to a better understanding of how RIPK1 kinase is regulated in health and disease. |
Start Year | 2016 |
Description | WRNIP1-mediated regulation of LUBAC |
Organisation | Albert Ludwig University of Freiburg |
Country | Germany |
Sector | Academic/University |
PI Contribution | Here we are investigating how one of the key E3 ligases (LUBAC) is regulated. This E3 ligase controls innate and adaptive immune signalling events and hence a better understanding of its regulation is a central question in medicine. We have identified a new interaction partner of LUBAC and have generated a knock-out animal that we plan to study in greater details. Since there exists redundancy among LUBAC regulatory processes we are investigating the possibility that WRNIP1 and SPATA2 might function redundantly with each other. |
Collaborator Contribution | Professor Uli Maurer will be crossing our WRNIP1-KO animals to animals deficient for SPATA2 and CYLD. Respective off spring will subsequently be analysed. |
Impact | not available yet. |
Start Year | 2022 |
Description | mass spectrometric identification of components of the TNF-receptor signalling complex |
Organisation | Canadian Institutes of Health Research |
Department | Institute of Cancer Research |
Country | Canada |
Sector | Public |
PI Contribution | We have provided purified samples for mass spectrometric analysis. |
Collaborator Contribution | Our collaborators have analysed our samples using state-of-the art mass spectrometry. Moreover, using Saint Analysis, this has helped us to identify putative binding partners of components of the TNF signalling complex. |
Impact | The manuscript that the reports these mass spectrometric findings has been accepted for publication Cell Reports. |
Start Year | 2014 |
Description | mass spectrometric identification of components of the TNF-receptor signalling complex |
Organisation | Max Planck Society |
Department | Max Planck Institute for Terrestrial Microbiology |
Country | Germany |
Sector | Academic/University |
PI Contribution | We have provided purified samples for mass spectrometric analysis. |
Collaborator Contribution | Our collaborators have analysed our samples using state-of-the art mass spectrometry. Moreover, using Saint Analysis, this has helped us to identify putative binding partners of components of the TNF signalling complex. |
Impact | The manuscript that the reports these mass spectrometric findings has been accepted for publication Cell Reports. |
Start Year | 2014 |
Description | mass spectrometric identification of components of the TNF-receptor signalling complex |
Organisation | University of Basel |
Department | Biozentrum Basel |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | We have provided purified samples for mass spectrometric analysis. |
Collaborator Contribution | Our collaborators have analysed our samples using state-of-the art mass spectrometry. Moreover, using Saint Analysis, this has helped us to identify putative binding partners of components of the TNF signalling complex. |
Impact | The manuscript that the reports these mass spectrometric findings has been accepted for publication Cell Reports. |
Start Year | 2014 |
Description | Awareness event at the House of Lords |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Talk and discussion groups brought together clinicians, fundamental biologists, researchers from pharmaceutical companies, policymakers and end users to discuss how breast cancer research, and novel treatment regiments, could be improved via a change in clinical practice for patient benefit. Apart from a positive feedback, there were no recordable impacts. |
Year(s) Of Engagement Activity | 2015,2016,2017,2018,2019,2020 |
Description | Cell Death Lectures |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Undergraduate students |
Results and Impact | The activity was to educate medical student and Vets about the different forms of cell deaths. |
Year(s) Of Engagement Activity | 2020,2021 |
Description | Chair of Site Visit review committee of the Nantes Cancer Research Centre |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | I was acting chair of the Science Review Panel for the Nantes Cancer Centre. |
Year(s) Of Engagement Activity | 2021 |
Description | Fundraising event at the Breast Cancer Now Research Centre |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | A series of fund raising events took place throughout these years, each event saw 20 -30 people taking part. Ongoing research was communicated orally, which led to lively exchanges of questions and answers Fundraisers liked the event, which prompted many repeat venues in which the current project was explained in great details |
Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015,2016,2017,2018,2019,2020,2023 |
Description | Lecture on Cell Death |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I was invited to give lectures on cell death. Below is a list of invited lectures of the last 5 years: 2023 University of Freiburg, Germany 2023 Life Science 2, University of Zürich, Switzerland 2023 University of Innsbruck, Austria 2023 University College London, UK 2022 Novartis Institutes for Biomedical Research, Basel, Switzerland 2022 Gordon Research Conference on Cell Death and Inflammation, Les Diablerets, Switzerland 2022 EMBO Conference on Ubiquitin and Ubiquitin-like proteins, Cavtat, Croatia 2022 EMBO workshop on phagocytosis, Ghent, Belgium 2022 EMBO workshop on Cell Death and Inflammation, Crete, Greece 2021 2nd Fusion Conference on Ubiquitin signalling in Health and Disease, virtual 2021 18th International TNF conference, Les Diablerets, Switzerland 2021 Virtually Dead Meeting, virtual 2020 Symposium 2020 - For2036, Obergurgl, Austria 2019 EMBO Workshop on Cell Death and Immunity, Crete, Greece 2019 Cold Spring Harbor Meeting on Cell Death, New York, USA 2019 Beatson International Cancer Conference, Glasgow, UK 2019 17th International TNF conference, Monterey, California, USA 2019 Cancer, Inflammation and Immunity Conference, Cambridge, UK 2019 EMBO Workshop on Pathogens and Signalling, Oxford, UK 2018 Swiss Apoptosis Meeting, Bern, Switzerland 2018 Gordon Research Conference on Cell Death, Maine, USA 2018 CDD Cancer and Cell Death conference, Cambridge, UK 2018 Technical University, Copenhagen, Denmark 2018 Fusion Conference on Ubiquitin signalling in health and disease, Bahamas 2018 Keystone Symposium on Cell Death, Inflammation and Adaptation to Tissue Stress, Breckenridge, Colorado, USA 2017 The Banbury Centre Cold Spring Harbor Laboratory Meeting on Regulated Necrosis - Pathways and Mechanisms, Banbury, USA 2017 Keystone Symposium on Cell Death and Immunity, Dublin, Ireland 2017 16th International TNF Conference, Singapore 2017 University of Milan, Italy 2017 University of Bath, UK 2017 EMBO workshop on Cell Death and Inflammation, Obergurgl, Austria 2017 Fusion Conference on Cell Death, Stress and Metabolism, Cancun, Mexico 2016 NCRI Cancer Conference, Liverpool, UK 2016 Gordon Research Conference on Cell Death, Spain 2016 'At the Cross-road' symposium, University of Cologne, Germany 2016 Cell Death and Inflammation, Crete, Greece 2016 European Cell Death Workshop, Rome, Italy 2016 NCRI cancer conference, Liverpool, UK 2016 Champalimaud Centre for the unknown, Lisbon, Portugal 2016 University of Cologne, Germany 2016 Cancer Course, University of Birmingham, UK 2016 University of Manchester, UK 2016 Max F. Perutz Laboratories (MFPL) Vienna, Austria 2016 Gulbenkian Institute, Lisbon, Portugal 2016 Gordon Research Conference on Ubiquitin, NF-kB and MAPK signalling, Whistler, Canada |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019,2020,2021,2022,2023 |
Description | Panel member of Barts Charity |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | As part of the Barts Charity grant review board, i am evaluating the quality and fundability of proposed Seed grants as well as Project grants. I am serving as active panel member in making funding decisions. |
Year(s) Of Engagement Activity | 2020,2021,2022,2023 |