Cell Death Signalling

Cell Death is one of the most important and fundamental processes in human development, health and disease.  Highly organised cell death signalling is needed to eliminate damaged cells and cells that have passed their ‘best before date’ from the body and is also important in killing potential tumour cells.  Too much or too little cell death can have major pathological consequences, such as the development of cancer.  In fact, one of the major challenges for cancer therapies is the resistance of many tumour cells to induction of cell death due to pro-survival signalling in the cancer cells.

news-example-1

events-example

Major Discoveries/advances:

Our research is :

  • Uncovering the intricate signalling pathways that mammalian cells use to communicate when they are stressed or destined to die.
  • Paving the way for improved interventions in cancer and other diseases where cell death goes wrong.
  • Below are some of the recent research advances made by our researchers:
In 2014, Dr Adrienne Gorman’s group discovered a mechanism by which cells can be rescued at a late stage in apoptosis (programmed cell death) (Mnich et al., Cell Death Dis, 2014).  This discovery has identified a new way to protect cells from what was previously considered the ‘point-of-no return’ from cell death, caspase activation.  This ‘point of no return’ in the apoptosis pathway involves mitochondrial outer membrane permeabilisation, which releases cytochrome c, triggering apoptosome formation and caspase activation, resulting in cell death.  In this study, Dr Gorman’s group found that nerve growth factor (NGF), an important pro-survival protein in nerve cells, can prevent apoptosis, even at a late stage, by removing active caspase-3.  In this way, NGF protects the cell from cell death.New-mechanisms-to-rescue-cells-from-death

discovery-of-the-stressosomeAlso in 2014, Professor Afshin Samali made a landmark discovery linking cell stress, autophagy (a process of cell recycling) and cell death (Deegan et al., Autophagy, 2014).  This discovery has altered our understanding of how cells die and has relevance for how we treat cancer cells.  Cancer cells often have defects in their cell death machinery that allows them to survive stress that would otherwise cause them to die.  Professor Samali’s group found that when cells with defects in their standard death machinery are put under prolonged stress, autophagosomes, the cell’s recycling plants, provide a platform to activate an alternative cell death pathway via caspase 8. This was the first time that this unique cell death-inducing complex was discovered, and Professor Samali’s group have termed it the ‘Stressosome’.

This research has important implications for cancer, as resistance to chemotherapy is a common problem in the treatment of cancer, and it is frequently caused by defects in the standard cell death machinery (mitochondrial death effector proteins). So, alternative stress-induced cell death pathways, such as the one discovered by Professor Samali’s group, may be particularly useful in tackling the problem of chemoresistance in cancer cells.

The research interest of Dr Eva Szegezdi’s laboratory is the regulation of death receptor signalling in healthy versus malignant (cancerous) cells. Her group focuses on the death ligand TRAIL, which is a signalling molecule used by immune cells to kill other cells (such as pre-cancerous cells) that may be dangerous to the body.  Dr Szegezdi discovered a mechanism that protects normal, non-cancerous cells from cell death induced by the death ligand, TRAIL (Van Dijk et al., Cell Death and Disease 2013).

Figure 5edit

The goal of Dr Howard Fearnhead’s research group is to get a better understanding of how cells, and particularly cancer cells, make life-and-death decisions (Connolly et al., Front Physiol., 2014, Jager et al., Biochem Res Int., 2012). His group was the first to show in 2008 that the mitochondrial apoptotic pathway induces a non-apoptotic outcome in muscle cells (Murray et al., J. Cell Science, 2008).  In this study, he showed that caspase-9, which is traditionally known as an initiator of cell death by mitochondrial apoptosis, also plays an important role in the development of muscle cells.  More recently, his group was the first to show a new role for DNA-dependent Protein Kinase (DNA-PK).  This kinase is known to initiate signalling cascades in response to DNA damage but Dr Fearnhead discovered that it is also important in muscle differentiation (Connolly and Fearnhead, FEBS J, 2016)

new-roles-for-cell-death-enzymes

Current Research:

Ongoing research at the Apoptosis Research Centre in the area of Cell Death Signalling includes:

  • Research to determine the role of death receptor signalling in tumour immune surveillance. (Dr Eva Szegezdi’s group)
  • Investigating the roles of the apoptotic death machinery during cell differentiation, tissue repair and tumourigenesis. (Dr Howard Fearnhead’s group)
  • Signalling involved in deciding between cell survival and cell death in cancer. (Dr Adrienne Gorman and Professor Afshin Samali’s group)
  • Understanding how Cell stress responses influence pro-inflammatory processes in cancer. (Dr Susan Logue)

Our Research Funders