Defining stroma function in the developing tumour microenvironment
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
Our immune system is our primary defence mechanism, but tumours have developed strategies to interfere with almost every step necessary for our immune system to recognise and destroy cancer cells. The recent success of immunotherapy, which aim to ‘kick start’ our immune system hold great promise, but currently are effective in just a few cancer types, with many patients not responding. Understanding how a tumour is able to evade and switch off our immune system during its development will be key to the development of improved treatments and the design of new, targeted therapies. A tumour contains many non-cancer cells that are critical to support the tumour as it develops. One of these populations, the cancer associated fibroblast, is emerging as a key promoter of tumour inflammation, but little is known about the how, when or who they act upon in a tumour, or how they prevent therapies from working. This programme uses state-of-the-art technologies to address these problems. Using such an integrative approach we aim to uncouple the networks governing the suppressive function of cancer-associated fibroblasts, and to exploit these findings to develop new or improved approaches to cancer therapy.
Technical Summary
Our immune system is our primary defence mechanism destroying both exogenous and endogenous threats, but tumours have developed strategies to interfere with almost every step necessary for a successful anti-tumour immune response. The recent success of immunotherapy platforms to harness and reactivate the immune response represent a major therapeutic advancement, however, current approaches are effective in just a few cancer types, and many patients still fail to respond or do not see lasting benefits. Increasing our understanding of anti-tumour immunity and the suppressive networks at play during the different stages of malignant transition will be fundamental to the development of improved strategies and design of new, targeted therapeutic platforms. The supporting tumour stroma, particularly cancer associated fibroblasts (CAFs) are emerging as key sources of tumour-promoting inflammation, but little is known about the mechanisms by which these cells act, when in tumour evolution these functions are acquired, or how they may contribute to therapeutic resistance. This programme takes a multidisciplinary approach, integrating experimental cancer models, complex in vitro and in silico systems, high throughput genomics and bioinformatics to explore the mechanisms and evolution of stromal-mediated immune dysfunction in the tumour microenvironment. Focusing on a subset of CAFs and their counterparts at tumour draining lymph nodes, which express the glycoprotein podoplanin, we aim to uncouple the immunoregulatory systems governing their suppressive function.
People |
ORCID iD |
Jacqueline Shields (Principal Investigator) |
Publications
Stewart GD
(2022)
A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA).
in British journal of cancer
Lakins MA
(2018)
Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells.
in Nature communications
Mazzaglia C
(2023)
Deployable extrusion bioprinting of compartmental tumoroids with cancer associated fibroblasts for immune cell interactions.
in Biofabrication
Shorthouse D
(2018)
Exploring the role of stromal osmoregulation in cancer and disease using executable modelling.
in Nature communications
Rodriguez-Rodriguez N
(2022)
Identification of aceNKPs, a committed common progenitor population of the ILC1 and NK cell continuum.
in Proceedings of the National Academy of Sciences of the United States of America
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_12022/4 | 01/10/2013 | 31/03/2018 | £882,000 | ||
MC_UU_12022/5 | Transfer | MC_UU_12022/4 | 01/10/2013 | 31/03/2022 | £1,713,000 |
MC_UU_12022/6 | Transfer | MC_UU_12022/5 | 01/10/2013 | 31/03/2022 | £2,157,000 |
MC_UU_12022/7 | Transfer | MC_UU_12022/6 | 01/10/2013 | 31/03/2022 | £2,147,000 |
MC_UU_12022/8 | Transfer | MC_UU_12022/7 | 01/10/2013 | 31/03/2022 | £5,896,000 |
MC_UU_12022/9 | Transfer | MC_UU_12022/8 | 01/10/2014 | 31/03/2022 | £869,000 |
MC_UU_12022/10 | Transfer | MC_UU_12022/9 | 01/01/2015 | 31/03/2022 | £987,000 |
Description | Endomagnetics - Longitudinal Study |
Amount | £28,443 (GBP) |
Organisation | Endomagnetics |
Sector | Private |
Country | United Kingdom |
Start | 07/2015 |
End | 07/2017 |
Description | Exploring Midl Magnetic Hyperthermia to treat tumours |
Amount | £71,848 (GBP) |
Organisation | Endomagnetics |
Sector | Private |
Country | United Kingdom |
Start | 03/2021 |
End | 03/2022 |
Description | Urological Malignancies Pump Priming Award |
Amount | £10,000 (GBP) |
Organisation | Cambridge Cancer Centre |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2021 |
Description | W. D. Armstrong Studentship - Modelling Lymph Node Metastasis on a Chip for Therapeutic Discovery |
Amount | £115,000 (GBP) |
Organisation | University of Cambridge |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2018 |
End | 03/2022 |
Title | Single cell atlas of the evolving mouse tumour environment |
Description | We have performed detailed single cell sequencing of the tumour microenvironment and draining lymph nodes at time points across development. Providing kinetic data of immune, non immune and lymph node populations. Data made freely available for researchers from data.Teichlab.org |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | Resource for researchers to use. |
URL | http://www.teichlab.org/data/ |
Description | Examining the contribution of microenvironmental elements to pathogenesis of oesophageal cancer |
Organisation | Medical Research Council (MRC) |
Department | MRC Cancer Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are examining how fibroblasts contribute to the malignant transformation of Barrett's esophagus. We brought expertise in fibroblasts biology and cell lines. Collaborators have provided tissue samples and we have worked together to establish culture models. |
Collaborator Contribution | Collaborators provided expertise in epithelial biology of OAC as well as tissue samples and cell lines. we have worked together to establish culture models. |
Impact | Non yet |
Start Year | 2021 |
Description | Immune cell mediated steroidogenesis - single cell sequencing |
Organisation | EMBL European Bioinformatics Institute (EMBL - EBI) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are proving tumour biology expertise, in vivo experimental approaches and intellectual input. Co-investigator on Cancer Research UK Tumour Immunology Grant |
Collaborator Contribution | Providing expertise on steroidogenesis, single cell sequencing platform and intellectual input. Co-investigator on Cancer Research UK Tumour Immunology Grant |
Impact | Ongoing project |
Start Year | 2015 |
Description | Lymphatic function and SPIO nanoparticles |
Organisation | Endomagnetics |
Country | United Kingdom |
Sector | Private |
PI Contribution | Providing mechanistic insight into function of research product based upon the expertise and models available within the research group |
Collaborator Contribution | Provision of research materials and intellectual input |
Impact | publication in a peer-reviewed journal Assistance with receiving FDA device exemption |
Start Year | 2014 |
Description | Modelling stromal function in tumour draining lymph nodes |
Organisation | University of Cambridge |
Department | MRC Cancer Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This a collaboration between computational biologists and wet lab experimentalists. We have performed experiments yielding large amounts of data that was analysed by them. Data from their was then used as a basis for their modelling systems, where their predictions were functionally verified by members of my lab |
Collaborator Contribution | This a collaboration between computational biologists and wet lab experimentalists. We have performed experiments yielding large amounts of data that was analysed by them. Data from their was then used as a basis for their modelling systems, where their predictions were functionally verified by members of my lab |
Impact | Riedel et al Nature Immunology 2016. This is a multidisciplinary collaboration crossing wet lab and in silica approaches |
Start Year | 2015 |
Description | Organ on a chip - modelling lymph node responses |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Joint PhD project with Dr Shery Huang to use microfluidic systems to model the responses of tumour draining lymph nodes. We provide the biological aspects of the project. Very much a mutual partnership |
Collaborator Contribution | Joint PhD project with Dr Shery Huang to use microfluidic systems to model the responses of tumour draining lymph nodes. Shery's side provide the engineering and manufacturing aspects of the project. Very much a mutual partnership |
Impact | none yet. Although we were awarded.a WD Armstrong Fellowship to support the student |
Start Year | 2018 |
Description | Pathology of Renal Cancer with VTT |
Organisation | University of Cambridge |
Department | Department of Oncology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are examining the role of the microenvironment in Renal Cancer with VTT. We have developed staining and sequencing protocols to comprehensively analysis the TME in disease and in response to therapy. We have received additional support with a CRUK CCC pump-priming award |
Collaborator Contribution | Collaborators have provided clinical samples and trial data |
Impact | We are writing the papers generated from data. Data has been presented at ASCO by clinical collaborators. |
Start Year | 2019 |
Description | Targeting Tumours by Magnetic Hyperthermia |
Organisation | Endomagnetics |
Country | United Kingdom |
Sector | Private |
PI Contribution | We aim to address the potential of applying MagSeed as targeted therapeutic adjuvants in the clinical setting through the induction of mild hyperthermia. Lab-based work and expertise to address the question |
Collaborator Contribution | Supply materials and equipment to facilitate work, and valuable intellectual input |
Impact | none yet. New project |
Start Year | 2021 |
Description | Cambridge Science Festival 2014 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Spoke to public about research and coordinated activities about the cell matrix Increased awareness of research |
Year(s) Of Engagement Activity | 2014 |
Description | MRC Open Day 2019 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Groups of A level students (typically in their first year) from schools within the Cambridge area took part in a practical exercise within my lab. After an introduction to the concepts and scope students received hands on experience of techniques we use routinely as part of our research. I was also participating in an interactive careers section to discuss longer term options out there. |
Year(s) Of Engagement Activity | 2018,2019 |
Description | Participation in Cambridge University Science Festival (2015-2019) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The Cambridge Science Festival aims to reach out to the general public and communicate about the different aspects of science and research being undertaken at the University. It is a free event, over two weeks, with an excess of 270 events and more than 50000 attendees last year. As part of this, the MRC CU along with other departments from the BioMedical Campus organised a set of talks and activities on the BioMed Campus day of the Festival that were attended by over 2000 people from all walks of life - from young children and young adults to parents/carers and professionals. The Shields lab was part of the MRC CU team at this event. The event generated a lot of interest in cancer research, helped raise awareness about the importance of 'early' in cancer which is the mission of the MRc CU and also led to a lot of interest being generated in the MRC Festival of Medical Research which followed on later in the year. |
Year(s) Of Engagement Activity | 2015,2016,2017,2018 |
URL | https://www.mrc-cu.cam.ac.uk/PublicEngagement/publicengagementhighlights |
Description | Participation in MRC Festival of Science Open Day 2016 at MRC CU |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 60 sixth-form students from across 8 schools in Cambridge visited the MRC Cancer Unit on the afternoon of the 22nd of June, 2016 for an Open Day. All students, accompanied by their teachers, were given a tour of the enitre building with an opportunity for engaging with researchers about the state of the art in cancer research and gaining hands-on experience with setting up experiments. Talks about career opportunities and challenges associated with pursuing cancer research were also available to all attendees. The event sparked a great deal of interest and enthusiasm in students and teachers alike and we have had a request for this event to be continued. We will be pursuing a similar format of activities for the MRC Science Festival in 2017, but reach out to more number of schools, including those outside of Cambridge city perimeters. |
Year(s) Of Engagement Activity | 2016 |
URL | https://mrccancerunit.wordpress.com/2016/07/06/inspiring-the-next-generation-of-cancer-researchers-t... |
Description | Pint of Science |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Pint of Sciences aim to communicate research to the general public in an informal setting - the pub. I talked about the "other cells of the tumour" to give the public an overview of the importance of the tumour microenvironment and how we may use this therapeutically in the future as part of the Combatting Cancer pint of Science event held in May 2019. The event was also shared with local artists who generated new pieces of artwork relating to our research having met with each presenter, discussed and interpreted our work. |
Year(s) Of Engagement Activity | 2019 |
URL | https://pintofscience.co.uk/event/combating-cancer |