Just as ‘no man is an island’, no cell in the human body can survive on its own. Our bodies are made up of billions of cells that interact physically and through various signalling mechanisms. Our immune system is a good example of how our cells work together in a coordinated approach to prevent infection, and seek out and eliminate foreign or damaged cells that may be dangerous to the body as a whole. Conversely, when cancer cells manage to evade the immune system, the cells surrounding the growing tumour (the tumour microenvironment) can play a role in protecting the tumour from immune cells, chemotherapy etc. Therefore, understanding the tumour microenvironment can be just as important as understanding the characteristics of the tumour itself in order to effectively target and kill these cancer cells.
Our research has led to numerous advances in understanding tumour microenvironments and the signalling that occurs between tumours and their surrounding tissues. For example:
Targeting Selectins and Their Ligands in Cancer (Natoni, Mccauley, O’Dwyer, Front Oncol. 2016)
Contribution: Pal Dhami, 2016, Drug Discovery Today review
Dr Eva Szegezdi’s research on tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown the importance of the tumour microenvironment in regulating TRAIL sensitivity. TRAIL is a death ligand known to be toxic to cancer cells but not to normal cells. TRAIL induces cell death by binding to two death receptors named Death Receptor 4 (DR4) and Death Receptor 5 (DR5), which sends a signal for the cell to die. However, TRAIL can also bind to inhibitory decoy receptors (DcR1 and DcR2), which, when expressed on the same cell as death receptors 4 or 5, can block the cell death signal. Dr Szegezdi’s research showed that decoy receptors also regulate TRAIL sensitivity at a tissue (multi-cellular) level and so represents a way in which the microenvironment can reduce the tumour’s sensitivity to TRAIL (O’Leary et al., Oncogene, 2016). Her research group used mathematical and laboratory models of the tumour microenvironment and found that decoy receptors not only act at an individual cell level, but they can also work by signalling between cells. Decoy receptors on stromal cells surrounding the tumour cells were found to have a potent inhibitory effect on the tumour tissue. This research highlights the need to overcome inhibitory signals from the tumour microenvironment in order to effectively kill tumour cells
Professor Michael O’Dwyer is interested in the carbohydrates called ‘glycans’ on the surface of cells and their involvement in cancer progression. The addition of glycans to the cell surface plays an integral role in regulating cell adhesion and trafficking (cell movement) to the bone marrow via cell-cell and cell-matrix interactions as well as influencing drug resistance and immune evasion. In 2014, Professor O’Dwyer’s group identified fo the first time an important role for sialyltransferases in the pathogenesis of multiple myeloma (Glavey et al., Blood, 2014).
They identified that high levels of the ST3GAL6 gene corresponded with worse survival for patients. They went on to show that sialyation is important in the migration and adhesion (‘homing’) of multiple myeloma cells to the bone marrow and, when the process of sialyation was blocked, it led to reduced homing to the bone marrow, smaller tumour size and better survival. This research represents a major advance in the field as it not only showed the importance of interactions between cells and the tumour micro-environment in the progression of cancer, but it also identified a target (sialyation and sialytransferases) for therapeutic drug development that could potentially reduce the influence of the tumour microenvironment and improve survival from this form of cancer. Subsequent work, in collaboration with US based company Glycomimetics, has established an important role for E-selectin in homing and resistance in multiple myeloma which has led to the first ever clinical trial evaluating an E-selectin inhibitor in multiple myeloma. Ongoing work is evaluating how sialylation can help multiple myeloma cells evade the immune system, with a focus on NK cells.
In 2013, Professor O’Dwyer and his colleagues at NUI Galway developed a laboratory-based system that mimics the microenvironment of chronic lymphocytic leukemia cells (Natoni, O’Dwyer, Santocanale, Methods Mo.l Biol., 2013). Chronic Lymphocytic Leukaemia (CLL) is currently an incurable disease that urgently needs new treatments. The tumour microenvironment is particularly relevant in CLL as CLL cells can build up in the bone marrow and lymphoid organs, making these cancer cells highly resistant to chemotherapy and allowing them to rapidly divide. The cell culture system developed by Professor O’Dwyer involves growing CLL cells alongside immune-like cells (similar to those found in lymph nodes), which partially mimics the tumour microenvironment of CLL. This system is highly useful for screening new drugs that may have potential against difficult-to-treat CLL cells.
Ongoing research at the Apoptosis Research Centre in the area of Tumour Microenvironment includes:
Dr Susan Logue:
- Ways in which the secretome (secreted signals) is regulated and how this, in turn, shapes the tumour microenvironment; how stress responses such as the unfolded protein response, alters the secretome (Dr Susan Logue’s group)
- Chemotherapy, while killing tumour cells, can also produce secreted factors (the secretome) that can make some cancer cells more resistant to therapy or can drive the expansion of cancer stem cells. Dr Logue is interested in finding out how chemotherapy can alter the secretome and ways in which we can try to combat this.
Professor O’Dwyer’s group:
- Understanding the role of selectin ligands and other sialylated structures in drug resistance and immune evasion.
- Development of novel strategies to increase the effectiveness of immune based therapies in multiple myeloma, including the use of cyclophosphamide to augment antibody dependent cellular phagocytosis and strategies to overcome moAb resistance