The first of the new research projects to receive funding following our call for proposals last year began in January at Bart’s Cancer Institute in London. The project, lead by Dr. Oliver Pearce, aims to identify how breast cancer tumours remodel their surroundings to protect them from attack by the bodies’ own immune system.
We know that sugar structures (glycans) are altered in cancer, we do not fully understand what types of glycan changes occur and how these changes protect the cancer cells from destruction by the immune system. Dr. Pearce hypothesizes that abnormal glycans in the extracellular matrix deactivate immune cells, turning off their cell-killing function. Through molecular analysis and assessment of the extracellular matrix, we hope to decode how immune cells are deactivated.
Through an understanding of the tumour extracellular matrix, and the glycan shield it displays, we hope to improve breast cancer treatment
Dr Oliver Pearce
This will be the first detailed study of the components that make up the extracellular matrix of triple negative breast cancer, including both the protein and sugar structures which we think may deactivate immune cells, stopping them from destroying the tumour.
The Glycan Shield
A defining feature of invasive cancer growth is the finger-like projections that invade healthy tissue. These are the result of a desmoplastic reaction of stromal cells in response to invading tumour cells. First there is breakdown of the tissue basement membrane, then expression of unusual extracellular matrix (ECM) proteins within the tumour microenvironment, TME. The resulting tumour ECM is important because it forms the scaffold in which the tumour grows and interacts with host cells.
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 TME. Towards this goal we recently carried out a detailed study of an evolving TME focusing on the ECM (Pearce et al, Cancer Discovery, 2017).
Here we identified the ‘Matrix Index’ (MI) a quantitative measure of the diseased ECM of high grade serous ovarian cancer. As part of this study we found that the MI appears to be common to many cancers, and was particularly strong in triple negative breast cancer (TNBC). The aim of this work is to further investigate the MI (described above) in triple negative breast cancer tissues, including characterizing the post-translational modifications on MI proteins, which we think are important in generating the immunosuppressive TME.
The information generated will provide the first high detailed study of the ECM of TNBC at both the translational and post-translational level. Unique matrix protein structures identified may have the potential for further development as prognostic biomarkers, or targeting molecules for the delivery of anticancer agents, or the target of therapeutic antibodies for matrix focused cancer therapies. This work will be done in collaboration with Dr. Alexandra Naba (University of Illinois, Chicago), Dr. Pedro Cutillas (QMUL), and Dr. Stuart Haslam (Imperial College, London).