Exploring Versican as an Immune Barrier in Cancer
Researchers: Dr Oliver Pearce and Priyanka Hirani (PhD student)
Location: Barts Cancer Institute, London
Dates: Dec 2019 – Dec 2023 Status: In progress
Funding: £17,500
Research Theme: Therapies, Detection
Aims
Alterations in the expression of glycans (sugars) in the tumour extracellular matrix (ECM) have been identified as a potential immune-barrier that protects cancer cells from destruction by the immune system.
Dr. Pearce hypothesises that one particular ECM molecule called Versican which is heavily decorated with glycans may be an important component of the immune-barrier. The project aims to investigate how Versican presence within triple negative breast cancer tissues associates with tumour immunity, and to determine whether Versican is a good target for boosting our bodies’ own immunity to fight cancer.
Background
The extracellular matrix is a scaffold of different molecules that make up the tissues surrounding cells. During invasive cancer growth, the tumour remodels the ECM by breaking down the tissue basement membrane and expressing unusual ECM proteins within the tumour microenvironment.
Compared to our understanding of malignant and immune cells, the tumour ECM and the cells that produce it are an under-investigated area of cancer biology. The identity, role in tumour progression, mechanisms of production, and therapeutic potential of the components that make up the tumour ECM are all important for our understanding of the tumour microenvironment.
Building on previous work from the project Characterising the Glycan Shield, the composition of ECM molecules has been identified and verified within triple negative breast cancer (TNBC) tissue samples. These molecules are strongly associated with suppressing the immune system and are prognostic markers of disease progression and outcome. Dr. Pearce’s lab hypothesises these ECM molecules play a direct role in disease progression and in particular in shielding tumours from our immune system and they may also inhibit current cancer treatments.
One identified ECM molecule is the proteoglycan Versican which Dr Pearce hypothesises is a key component of the tumour-induced immune barrier. To test this hypothesis PhD student Priyanka Hirani is undertaking an in-depth tissue analysis of Versican with a particular focus on how Versican expression associates with tumour immunity.
Priyanka is also exploring how the glycans that decorate Versican may change in disease which may be important for understanding how Versican is functioning in cancer. This second part is being done in collaboration with Prof. Tom Wight and Dr. Kim Alonge at the Benaroya Institute, Seattle, USA. Understanding how Versican functions in cancer may help identify ways to improve our bodies anti-tumour immunity.
Potential benefit for patients
Currently, immunotherapy treatment for solid tumours such as triple negative breast cancer, only works well in around 10-15% of patients. Targeting the ECM is a promising approach to improve immunotherapy response rates for all patients. Currently there are no identified ECM targets or approved clinical treatments so it is an exciting new therapeutic area.
Identifying a targetable motif on Versican could be the basis for future therapies to improve tumour immunity and immunotherapy response. This approach could mean more patients will benefit from long-term progression-free survival.
Publications
Mouse ovarian cancer models recapitulate the human tumor microenvironment and patient response to treatment. Maniati, E., Berlato, C., Gopinathan, G., Heath, O., Kotantaki, P., Lakhani, A., McDermott, J., Pegrum, C., Delaine-Smith, R. M., Pearce, O. M. T., Hirani, P., Joy, J. D., Szabova, L., Perets, R., Sansom, O. J., Drapkin, R., Bailey, P., Balkwill, F. R. Cell Rep, 2020, 30, 525-540.
Versican-A Critical Extracellular Matrix Regulator of Immunity and Inflammation. Wight, T. N., Kang, I., Evanko. S. P., Harten, I. A., Chang, M. Y., Pearce O. M. T., Allen C. E., Frevert C. W., Front Immunol 2020, 24, 512.
Targeting Versican as a Potential Immunotherapeutic Strategy in the Treatment of Cancer. Priyanka Hirani, Valentine Gauthier, Carys E. Allen, Thomas N. Wight and Oliver M. T. Pearce. Front. Oncol. 2021, 11:712807.