The focus of our research is the tumour microenvironment (TME). We are particularly interested in understanding the composition and function of the tumour extracellular matrix in immunosuppression.
Deconstructing a metastatic human tumor microenvironment. Cancer Disc (2018) 3, 304-319. PMID: 29196464
Characterization of the extracellular matrix of normal and diseased tissues using proteomics. J Proteome Res (2017) 16, 3083-3091. PMID: 28675934
A red meat-derived glycan promotes inflammation and cancer progression. PNAS (2015) 112, 542-547. PMID: 25548184
Engagement of myelomonocytic Siglecs by tumor-associated ligands regulates innate immune responses to cancer. PNAS (2014) 111, 14211-14216. PMID: 25225409
We are investigating the composition and function of the tumour extracellular matrix, which has been identified as a barrier to immunotherapy response. Our overall goal is to target this barrier to improve patient response rates to immunotherapy. Towards this goal we are characterizing the tumour extracellular matrix and developing 3D tumour models for functional studies. The lab uses a combination of molecular biology, biochemistry, and genetic engineering approaches.
To study the tumour microenvironment, our lab has developed some methodology and technology that is unique to our lab.
Matrisome proteomics and glycomics. Up until quite recently it was difficult to characterise the tissue composition of tumour tissues. We use a matrisome proteomics approach to characterise the composition of tumour tissue at the translational (protein) level and the post-translational (glycan) level. We use these types of information to identify potential molecules within the tumour microenvironment that might play an active role in disease progression.
Engineered 3D tumour microenvironments. To test the role of our target molecules we use several 3D in vitro tumour models made from primary human cancer tissues. These provide a physiologically relevant and semi high throughput platform to exploring tumour progression, tumour immunity, and emerging biological therapies.
Bioinformatics. We use informatic approaches to analyze our characterization data sets. In particular we integrate protein and glycan data as a way to identify highly disease specific markers called ‘glycoforms’.
Current research projects:
In our previous studies, we have deconstructed the TME of high grade serous ovarian cancer (HGSC) and identified twenty-two ECM molecules that we use as a quantified ratio or 'matrix index', MI, found to be common in many human carcinomas (Pearce, Delaine-Smith, Maniati, et al. 2018). A major finding from this work has been the strong correlation of the MI with immunosuppressive immune cell phenotypes and poor prognosis in solid tumour patients. Understanding how the ECM disrupts anti-tumour immunity and regulates the local immune environment could identify new targets to treat many cancers. Our hypothesis is, components of the MI communicate with tumour infiltrating immune cells to generate immunosuppressive phenotypes. This work is being done by Elliott Puttock, in collaboration with Dr. Ann White at UCB Pharma.
Complementary to project 1, the aim of this work is to further investigate the MI (described above) in triple negative breast cancer tissues, including characterising the post-translational modifications on MI proteins, which we think are important in generating the immunosuppressive TME. This work is being done by Ying Liu and Priyanka Hirani in my lab, and in collaboration with Dr. Alexandra Naba (University of Illinois, Chicago), Dr. Pedro Cutillas (QMUL), and Dr. Stuart Haslam (Imperial College London).
As a result of research project 2, we have identified one particular matrix index molecule that associates with inhibition of cytotoxic T-cell infiltration within the tumour microenvironment. Taking a biochemical approach we are following up on this observation to characterise the proteoglycans structure and immunological function. This work is being done by Priyanka Hirani in my lab, in collaboration with Dr. Pedro Cutillas (BCI), and Prof. Tom Wight (Benaroya Research Institute, Seattle).
Building in vitro 3D human multicellular models of high-grade serous ovarian cancer Malacrida B, Pearce OMT, Balkwill FR STAR Protocols (2022) 3(7)
Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion Murray ER, Menezes S, Henry JC et al. Cell Reports (2022) 38(7)
Tgfbi production by macrophages contributes to an immunosuppressive microenvironment in ovarian cancer Lecker LSM, Berlato C, Maniati E et al. Cancer Research (2021) 81(7) 5706-5719
Targeting Versican as a Potential Immunotherapeutic Strategy in the Treatment of Cancer Hirani P, Gauthier V, Allen CE et al. Frontiers in Oncology (2021) 11(7)
A human multi-cellular model shows how platelets drive production of diseased extracellular matrix and tissue invasion Malacrida B, Nichols S, Maniati E et al. iScience (2021) 24(7)
Modelling TGFβR and Hh pathway regulation of prognostic matrisome molecules in ovarian cancer Delaine-Smith RM, Maniati E, Malacrida B et al. iScience (2021) 24(7)
Mechanical stimulation modulates osteocyte regulation of cancer cell phenotype Verbruggen SW, Thompson CL, Duffy MP et al. Cancers (2021) 13(7)
Basement membrane stiffness determines metastases formation Reuten R, Zendehroud S, Nicolau M et al. Nature Materials (2021) 20(7) 892-903
A sweet approach to heat up cancer response to immunotherapy Pearce OMT, Läubli H Cancer Discovery (2020) 10(7) 1789-1790
FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer Zaghdoudi S, Decaup E, Belhabib I et al. EMBO Molecular Medicine (2020) 12(7)For additional publications, please click here
Dr Elly Tyler
Mr Elliott Puttock, Ms Ying Liu, Ms Priyanka Hirani, Ms Valentine Gauthier
I originally trained as an organic chemist with Prof Ben Davis and Prof Len Seymour at Oxford University. My PhD thesis was on the development of chemically glycosylated viral vectors for cancer gene therapy.
For my post-doctoral studies I moved to Prof. Ajit Varki’s lab at the University of California, San Diego. Here I investigated how glycans are involved in cancer immunity. After five years in California, I returned to the UK for a second post-doc with Prof. Fran Balkwill at Barts Cancer Institute to further train in cancer biology.
In September 2017 I started my own research program with funding from UCB Pharma and Against Breast Cancer. The theme of our work is the tumour matrisome and its role in tumour immunity.