Detection

How to design better tools for earlier diagnosis of secondary breast cancer to increase survival rates.

The Glycan Shield

Dr Oliver Pearce, Barts Cancer Institute, London

The Glycan Shield projectat Barts Cancer Institute in London 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

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.

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).

Investigating how breast cancer cells survive chemotherapy by hiding in plain sight

Professor Ingunn Holen, University of Sheffield

In order to improve outcome for breast cancer patients, we need to understand how some cancer cells avoid being killed by chemotherapy, remaining in the body and causing the cancer to return, often many years later.

This is the focus of research carried out by the team of Professor Ingunn Holen at the University of Sheffield, supported by seed funding from Against Breast Cancer. The funding supports a project to establish how breast cancer cells survive treatment by entering a dormant state, meaning that they are no longer sensitive to chemotherapy that is designed to eliminate cancer cells that grow and divide. By staying dormant, the cancer cells are hiding in plain sight, mainly in the bone marrow. Some of these dormant cancer cells may one day be triggered to start to grow and form new colonies, as well as spread to other parts of the body.

We don’t yet understand the mechanisms that cancer cells rely on to survive in this dormant state, or what triggers them to start growing again. The Sheffield project will study this important dormancy process to try and identify novel therapies that can either eliminate dormant cancer cells, or ensure they remain dormant indefinitely.

The ultimate aim of this research is to develop anti-dormancy therapies that will prevent breast cancer recurrence and spread, thereby improving the outcomes for patients.

Publications

Serum IgA1 shows increased levels of α2,6-linked sialic acid in breast cancer Hannah J. Lomax-Browne , Claire Robertson , Aristotelis Antonopoulos , Anthony J. C. Leathem , Stuart M. Haslam , Anne Dell & Miriam V. Dwek, (2019) The Royal Society Interface Focus 9(2)

Cadherin-5: a biomarker for metastatic breast cancer with optimum efficacy in oestrogen receptor-positive breast cancers with vascular invasion Fry, S. A., C. E. Robertson, R. Swann and M. V. Dwek (2016) Br J Cancer 114(9): 1019-1026

A targeted glycoproteomic approach identifies cadherin-5 as a novel biomarker of metastatic breast cancer Simon A. Fry, John Sinclair, John F. Timms, Anthony J. Leathem, Miriam V. Dwek Cancer Lett. 2013 Jan 28;328(2):335-44

A novel approach to determining the affinity of protein-carbohydrate interactions employing adherent cancer cells grown on a biosensor surface. Peiris D, Markiv A, Curley GP, Dwek MV. Biosens Bioelectron. 2012 May 15;35(1):160-6.

The lectin Helix pomatia agglutinin recognizes O-GlcNAc containing glycoproteins in human breast cancer. Rambaruth ND, Greenwell P, Dwek MV. Glycobiology. 2012 Jun;22(6):839-48

Lectin array based strategies for identifying Metastasis-Associated changes in Glycosylation Fry S, Afrough B, Leathem AJ, Dwek MV. Methods in Molecular Biology 2012; (878):267-272

2DE- based proteomics for the analysis of metastasis associated proteins. Metastasis Research Protocols Dwek MV, Peiris D. Methods in Molecular Biology 2012; (878):111-120

Functionalization of single-walled carbon nanotubes and their binding to cancer cells Madani. SY, Tan A, Dwek MV, Seifalian AM. International Journal of Nanomedicine 2012; 7:1-10

Beyond the genome and proteome: targeting protein modifications in cancer Markiv A, Rambaruth NDS, Dwek MV. Current Opinions in Pharmacology 2012 Aug;12(4):408-13

Cell surface glycan-lectin interactions in tumor metastasis Rambaruth ND, Dwek MV. Acta Histochem. 2011 Oct;113(6):591-600

Identification cloning and characterization of two N-acetylgalactosamine binding lectins from the albumen gland of Helix pomatia Markiv A, Peiris D, Curley P, Odell M, Dwek MV. Journal of Biological Chemistry 2011 Jun 10;286(23):20260-6