Cell death is a crucial process in development, homeostasis and (patho)physiology. In normal conditions about 100 billion cell die mostly by apoptosis. However, many diseased conditions are associated with a deregulated balance in cell death. Too much or too sensitive cell death is associated with inflammatory and degenerative diseases, while too little or too insensitive cell death is associated with development of cancer and with therapeutic resistance. This implies that depending on the particular role of cell death in a given disease therapeutic strategies could be envisioned that either sensitize or desensitize cell death pathway. However, in order to do so, a profound knowledge is required not only of cell death pathway but also on the molecular mechanism that regulate these cell death pathways.

The research unit of Peter Vandenabeele focuses on the molecular mechanisms of different cell death modalities (a.o. apoptosis, necroptosis, ferroptosis, immunogenic cell death) and cellular stress (ER stress), their regulation, their functional interactions and the role herein of caspases, RIPK and other signalling molecules. The unit is both interested in cell autonomous as well as intercellular aspects of cell death and cellular stress such as communication with the innate immune system. These processes are studied in an integrated way at the level of biochemistry, cell biology, development of conditional transgenic models and their role in various diseases models such as sepsis, skin inflammation and cancer, and intestinal inflammation and cancer. In order to identify novel targets in signalling of cell death modalities we developed a cellular screening platform in which we screen customized functional classes of libraries of sh/siRNAs (kinases, ubiquitylating enzymes, etc.), libraries of known clinical drugs and series of chemical compounds. The hits are then further examined in cellular systems and in experimental disease models for their potential to modulate cell death pathways or to influence disease models.

In the Bertrand subgroup, we focus on the elucidation of the molecular mechanisms regulating stress-induced cell survival/death, as well as innate immune/inflammatory responses, with a particular interest on the role of post-translational modifications, such as phosphorylation and ubiquitylation. This group is currently characterizing the cell death checkpoints (apoptotic and necroptotic) downstream of TNFR1, as well as identifying new regulators of death induced by endoplasmic reticulum (ER) stress.

In the Declercq subgroup we mainly focus on understanding the role of RIPK1, 3 and 4 and MLKL in inflammation and cancer in the skin. Therefore we make use of cellular models and in vivo mouse models. We are especially interested in investigating whether RIPK1, RIPK3 or MLKL can serve as therapeutic targets in skin inflammation. In addition, we investigate the functions of RIPK4 and secondary modifications controlling its activity.

In the Riquet subgroup, we are interested in biosensing and visualizing in a dynamic way complex formation, proteolysis and kinase activity during different forms of cellular stress and cell death. As a proof of concept we want to reveal the dynamics of RIPK1, RIPK3, and MLKL complex formation and activation in the initiation and execution phase of necroptosis in living cells and later in vivo. The dynamics and the visualization of these processes provide us with fundamental insights in the timing and subcellular localization of these processes in different cellular conditions, and might be very useful to think about therapeutic strategies and to validate the activity of novel and existing drugs.

Our fundamental research may lead to therapeutic applications in cancer, inflammatory and neurodegenerative diseases, and skin pathologies.

The work of the group of Vandenabeele has been described in several press releases like Knack, EOS Wetenschap and illustrated on YouTube.