Molecular Mechanisms of Cell Death
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
Diseases such as cancer and neurodegenerative disorders are characterised by a significant alteration in the total number of cells within the tissue. This may result from increased division of cells and/or may arise from a defect in cell death regulation. In tissues, such as the lymphoid system or the colon, cell death is very important as it controls the total number of cells within that tissue, whereas in the nervous system inappropriate cell death is catastrophic. Consequently, cell death in these situations is tightly controlled and often occurs in an ordered manner by a process called ‘apoptosis’, or a more recently identified mode of cell death termed ‘necroptosis’. We are studying these cell death processes because to successfully treat many diseases (e.g. cancer) it is important that we find ways to switch ‘ON’ cell death. However, it is crucial to first understand the basic mechanisms that regulate cell death in order to identify ways of selectively killing target cells while leaving most healthy cells unharmed. We are therefore trying to understand the fundamental mechanisms that regulate the response of target cells and normal cells to cytotoxic agents, as this will help in establishing the ideal choice agents for the treatment of disease. Our aim is to establish better predictive models of mitochondrial toxicity, providing mechanistic frameworks to facilitate safer drug development and potentially alleviate the toxic effects of existing treatments.
Technical Summary
Cell death is a fundamental cellular response that plays a crucial role both during development and in the removal of unwanted or damaged cells following stress, injury or infection. Inappropriate cell death regulation contributes to many human diseases, including cancer and autoimmune and neurodegenerative disorders. Proteins/pathways that control cell death have also been identified as defined nodes that form key decision points to regulate the response to toxic insult.
This Programme aims at understanding the fundamental mechanisms of cell death that regulate life/death decisions at the cellular level. By understanding the underlying molecular and cell biology of these processes, we aim to deliver field-changing mechanistic insights into toxicology and disease.
Our research Objectives are to develop a number of strategies including develop a number of strategies including novel ‘in vitro’ reconstituted models which, combined with an integrated molecular, cell biological and proteomics-based approach, place us in a prime position to examine the molecular determinants of cell death.
In particular, we will employ cutting-edge technologies to:
1. obtain novel insights on the regulation and molecular architecture of multiprotein signalling complexes that direct cell fate
2. define signalling networks conferring drug-induced mitochondrial toxicity or cell survival in translational models of hepatotoxicity
3. selectively target nodes of resistance to cell death in patient-relevant 3D tumour models.
The data generated through these integrated approaches will provide novel insights into the fundamental mechanisms of cell death that underlie the response to toxic injury, thus informing strategies to mitigate toxicity of existing therapies as well as newer agents under development.
This Programme aims at understanding the fundamental mechanisms of cell death that regulate life/death decisions at the cellular level. By understanding the underlying molecular and cell biology of these processes, we aim to deliver field-changing mechanistic insights into toxicology and disease.
Our research Objectives are to develop a number of strategies including develop a number of strategies including novel ‘in vitro’ reconstituted models which, combined with an integrated molecular, cell biological and proteomics-based approach, place us in a prime position to examine the molecular determinants of cell death.
In particular, we will employ cutting-edge technologies to:
1. obtain novel insights on the regulation and molecular architecture of multiprotein signalling complexes that direct cell fate
2. define signalling networks conferring drug-induced mitochondrial toxicity or cell survival in translational models of hepatotoxicity
3. selectively target nodes of resistance to cell death in patient-relevant 3D tumour models.
The data generated through these integrated approaches will provide novel insights into the fundamental mechanisms of cell death that underlie the response to toxic injury, thus informing strategies to mitigate toxicity of existing therapies as well as newer agents under development.
Organisations
- University of Cambridge (Lead Research Organisation)
- Cancer Research Technology (CRT) (Collaboration)
- Canadian Institutes of Health Research (Collaboration)
- UNIVERSITY OF ABERDEEN (Collaboration)
- UNIVERSITY OF LEICESTER (Collaboration)
- Cardiff University (Collaboration)
- MRC-Technology (Collaboration)
- Newcastle University (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
People |
ORCID iD |
Publications
Anderson GSF
(2022)
Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma.
in Blood
Chernova T
(2022)
Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells.
in International journal of molecular sciences
Collins A
(2021)
Development of a patient-derived explant model for prediction of drug responses in endometrial cancer.
in Gynecologic oncology
Collins A
(2020)
Patient-derived explants, xenografts and organoids: 3-dimensional patient-relevant pre-clinical models in endometrial cancer.
in Gynecologic oncology
Estornes Y
(2018)
N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis.
in Cell death & disease
Felley-Bosco E
(2018)
Asbestos: Modern Insights for Toxicology in the Era of Engineered Nanomaterials
in Chemical Research in Toxicology
Fox JL
(2021)
Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate.
in Nature communications
Galluzzi L
(2018)
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.
in Cell death and differentiation
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00025/1 | 01/04/2018 | 31/07/2020 | £1,680,000 | ||
MC_UU_00025/2 | Transfer | MC_UU_00025/1 | 01/04/2018 | 30/09/2020 | £3,488,000 |
MC_UU_00025/3 | Transfer | MC_UU_00025/2 | 01/04/2018 | 31/03/2024 | £2,873,000 |
MC_UU_00025/4 | Transfer | MC_UU_00025/3 | 01/04/2018 | 31/03/2024 | £3,108,000 |
MC_UU_00025/5 | Transfer | MC_UU_00025/4 | 01/04/2018 | 31/03/2024 | £2,200,000 |
MC_UU_00025/6 | Transfer | MC_UU_00025/5 | 01/04/2018 | 31/05/2019 | £76,000 |
MC_UU_00025/7 | Transfer | MC_UU_00025/6 | 01/04/2018 | 31/03/2024 | £2,547,000 |
MC_UU_00025/8 | Transfer | MC_UU_00025/7 | 01/10/2019 | 31/03/2024 | £2,438,000 |
MC_UU_00025/9 | Transfer | MC_UU_00025/8 | 01/09/2019 | 31/03/2024 | £1,721,000 |
Description | AZ iMED PostDoctoral Funding Scheme |
Amount | £200,000 (GBP) |
Organisation | AstraZeneca |
Department | Research and Development AstraZeneca |
Sector | Private |
Country | United Kingdom |
Start | 08/2017 |
End | 07/2020 |
Description | BBSRC I-CASE Award (with GSK) |
Amount | £118,126 (GBP) |
Funding ID | BB/M502819/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2014 |
End | 09/2018 |
Description | Integrated Analysis in Mouse and Man for Early Detection of Mesothelioma: IAMMED-Meso |
Amount | £2,069,250 (GBP) |
Funding ID | EDDPGM-Nov21\100001 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2022 |
End | 05/2027 |
Description | LLR Project Grant (Understanding the role of elF4B in the pathogenesis of Diffuse Large B-Cell Lymphoma) |
Amount | £170,616 (GBP) |
Funding ID | 14023 |
Organisation | Leukaemia and Lymphoma Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2015 |
End | 12/2018 |
Description | MRC ITTP Studentship Award |
Amount | £105,000 (GBP) |
Organisation | MRC Doctoral Training Program |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2023 |
End | 09/2027 |
Description | National Productivity Infrastructure Fund Sudentship Award with AZ R&D |
Amount | £90,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2017 |
End | 09/2021 |
Description | PREDICT-Meso: PRE-malignant Drivers Combined with Target-Drug validation in Mesothelioma |
Amount | £4,025,330 (GBP) |
Funding ID | 29372 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 02/2026 |
Description | Partnership between MRC-UoL-CRT and now MRC Technology (LifArc) for develpment of 3D Tumour Explant Platform |
Amount | £350,000 (GBP) |
Organisation | MRC-Technology |
Sector | Private |
Country | United Kingdom |
Start | 01/2018 |
End | 12/2023 |
Description | REMIT: Reconstructing the in vivo Evolution of mesothelioma for Improved Therapy |
Amount | £2,121,000 (GBP) |
Funding ID | DRCRPG-Jun22\100007 |
Organisation | Cancer Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2023 |
End | 03/2028 |
Title | Locus Specifc Database (LSBD) titled DRdb |
Description | We have generated the very first Locus Specific Database (LSVD) housing all known Variants of the TRAIL Receptors. This is a publically available database providing invaluable identifiable information on the pathogenic potential of TRAIL-R variants |
Type Of Material | Technology assay or reagent |
Year Produced | 2012 |
Provided To Others? | No |
Impact | Collaborative Manuscript currently in preparation |
Title | Reconstituted DISC Model |
Description | Over the last 5 years we have developed a novel in vitro reconstituton model of a siganaling complex called the DISC which regulates the susceptibility of cells to apoptosis induced by death ligands such as CD95 or TRAIL. This novel in vitro DISC model enables us to examine the key steps that regulate DISC formation and activity in both normal and tumour cells. This model was recently published in Molecular Cell (PubMed ID# 19683492), a patent has been filed by MRCT (A856/2276) and this information was also highlighted in an MRC Media Release (MRC/52/09) and the MRC Annual Review, 2009-2010. |
Type Of Material | Technology assay or reagent |
Year Produced | 2009 |
Provided To Others? | No |
Impact | This tool could provide a screen to assay for small molecule regulators of DISC activity so it has the potential not only to provide fundmental mechansistic insights but also identify potential novel regulators of DISC activity using a HTP approach and is amenable to kit formulation. |
Title | Locus Specifc Database (LSBD) titled DRdb |
Description | We have generated the very first Locus Specific Database (LSVD) housing all known Variants of the TRAIL Receptors. This is a publically available database providing invaluable identifiable information on the pathogenic potential of TRAIL-R variants |
Type Of Material | Database/Collection of data |
Year Produced | 2012 |
Provided To Others? | Yes |
Impact | Manuscript currently in preparation |
Description | Characterisation of the Ripoptosome Complex Induced by Genotoxic Stress |
Organisation | Canadian Institutes of Health Research |
Department | Institute of Cancer Research |
Country | Canada |
Sector | Public |
PI Contribution | Provided expertise on characterising large cell death signalling complexes. Experiments to characterise the Complex by gel filtration, IP and Western blotting. |
Collaborator Contribution | Publication of joint reserach paper in Molecular Cell (2011). Collaboration ongoing |
Impact | Joint research publication (Mol Cell) |
Start Year | 2011 |
Description | Explant Platform |
Organisation | Cancer Research Technology (CRT) |
Country | United Kingdom |
Sector | Private |
PI Contribution | We initially established the Explant Platform using either normal breast tissue (following breast reduction surgery) or surgically-resected breast tumour tissue with the Aim of testing the sensitivity of tumour cells within their 3D microenvironment to novel chemotherapeutics. |
Collaborator Contribution | In 2016, CRT and UoL (LD3) each committed 1 PDRA position, with accompanying consumables, for an initial period of 12 months (Total = 2 PDRAs) In 2017, MRCT (LifeArc) committed 2PDRA positions with accompanying consumables and CRT committed a further ! PDRA, with accompanying consumables for a period of 2 years. |
Impact | This collaboration has began in February 2016 and is ongoing |
Start Year | 2016 |
Description | Explant Platform |
Organisation | MRC-Technology |
Country | United Kingdom |
Sector | Private |
PI Contribution | We initially established the Explant Platform using either normal breast tissue (following breast reduction surgery) or surgically-resected breast tumour tissue with the Aim of testing the sensitivity of tumour cells within their 3D microenvironment to novel chemotherapeutics. |
Collaborator Contribution | In 2016, CRT and UoL (LD3) each committed 1 PDRA position, with accompanying consumables, for an initial period of 12 months (Total = 2 PDRAs) In 2017, MRCT (LifeArc) committed 2PDRA positions with accompanying consumables and CRT committed a further ! PDRA, with accompanying consumables for a period of 2 years. |
Impact | This collaboration has began in February 2016 and is ongoing |
Start Year | 2016 |
Description | Investigating the Potential Adverse Effects of Novel IAP Antagonists |
Organisation | Newcastle University |
Department | Institute of Cellular Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Molecular analysis of cell death activity of IAP antagonists |
Collaborator Contribution | Newcastle - access to pluripotnet liver cells/animal models |
Impact | MRC ITTP Studentship Award 2012-2017 |
Start Year | 2012 |
Description | Investigating the Potential Adverse Effects of Novel IAP Antagonists |
Organisation | University of Aberdeen |
Department | Division of Applied Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Molecular analysis of cell death activity of IAP antagonists |
Collaborator Contribution | Newcastle - access to pluripotnet liver cells/animal models |
Impact | MRC ITTP Studentship Award 2012-2017 |
Start Year | 2012 |
Description | Structural Modelling of Death Receptor Signalling Platforms |
Organisation | University of Leicester |
Department | Department of Molecular and Cell Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Intellectual Input on Death Receptor Signalling Platforms |
Collaborator Contribution | Structural Modelling of Death Receptor Signalling Components |
Impact | Manuscript Published in Molecular Cell - ID 22683266 |
Start Year | 2009 |
Description | Targeting c-FLIP |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have extensive experience in defining the mode of c-FLIP:Caspase-8 interactions in the context of the DISC and other key cell death/survival signalling platforms. |
Collaborator Contribution | Cardiff University will provide novel candidate small molecules that may target c-FLIP:Caspase-8 interaction. |
Impact | This collaboration was initiated in March 2016 and is ongoing |
Start Year | 2016 |
Description | The role of Mcl-1 in the co-ordinated regulation of apoptosis and autophagy |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | We have extensive expertise in exploring the fundamental mechanisms of cell death and autophagy and thus will provide valuable novel insight to this area of research within GSK Toxicology division. |
Collaborator Contribution | GSK have available a number of tool compounds that have exhibited potential adverse effects in tissues where the underlying mechanisms of toxicity appear centred around the regulation of apoptosis and autophagy at the level of mitochondria by the anti-apoptotic protein Mcl-1. |
Impact | This collaboration has just started - Oct 2014 |
Start Year | 2014 |
Title | Receptor-specific TRAIL Variants (PCT/GB2006/004461) |
Description | TRAIL Mutants designed within the MRC Toxicology Unit and patented by MRCT are currently being tested in relevant preclinical models of breast cancer. Previous work has provided proof of concept of the efficacy of these TRAIL Mutants in primary haematological malignancies and identified a critical requirement for employing TRAIL-R1-specific mutant forms of TRAIL in any potential therapy employing soluble TRAIL in these patients. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2010 |
Development Status | On hold |
Impact | Our work to date, plus our ongoing studies funded by the MRCT DGF in preclinical models of breast cancer, have helped provide a rational approach to optimize TRAIL therapy (either alone or in combination). |
Title | Reconstituted DISC Invention (IDF Ref# A856/2276) |
Description | Reconstituted DISC Model being developed for use in a kit format for potential commercialization to assess the impact of key mutations in DISC components that are associated with human disease. |
Type | Diagnostic Tool - Non-Imaging |
Current Stage Of Development | Initial development |
Year Development Stage Completed | 2010 |
Development Status | On hold |
Impact | MRCT have received interest from the commercial sector for a reconstituted DISC in 'kit format' |