Periodic Reporting for period 2 - DESTRESS (Death Receptors as Integrators of Stress-induced inflammation)
Berichtszeitraum: 2023-04-01 bis 2024-09-30
Many diseases are associated with chronic long-term inflammation (e.g. cancer, obesity, neurodegeneration, diabetes), which does not have an obvious infectious or acute injury cause, but is an exacerbating factor in these conditions. Instead, these diseases are frequently associated with persistent cell stress that is likely to act as a key driver of inflammation in these settings. However, how inflammation is initiated in response to cell stress remains enigmatic. Here, we will explore the nature of the molecules that sense and promote stress-induced inflammation, which we have dubbed 'SAMPs' (Stress-Associated Molecular Patterns). In particular, we will explore whether members of the TNF family act as integrators of divergent forms of cell stress, leading to inflammation. Understanding how cell stress promotes inflammation would open up a new frontier in inflammation research and would suggest new molecular targets for the treatment of chronic inflammation in multiple disease states.
To understand how stress-induced inflammation operates, we have used a number frequently encountered forms of cell stress, including (a) chemotherapeutic drugs that cause DNA damage (e.g. cisplatin, etoposide, doxorubicin and others), (b) chemotherapeutic drugs that trigger protein misfolding (bortezomib, carfilzomib), (c) and ‘BH3 Mimetic’ targeted chemotherapeutic agents that promote mitochondrial stress (Venetoclax, Navitoxlax) and have explored how these widely used drugs promote inflammation. We have discovered that death receptors play a key role in driving inflammation downstream of DNA damage. We have also discovered two novel pathways of inflammation triggered by protein misfolding stress and mitochondrial stress. Furthermore, we have also identified a new way that senescent cells (which are suspected to be a detrimental source of inflammation in tumors) may be eliminated in a therapeutic setting. We are currently exploring how to translate this approach into a therapeutically viable strategy. We have also discovered fundamental connections between the regulation of apoptosis and entry to premature replicative senescence (a cellular state that is often an undesirable outcome of chemotherapy).
We have made important breakthroughs into our understanding of how inflammation is initiated in response to DNA damaging chemotherapeutic drugs. We have also made important breakthroughs in our understanding of how molecular decisions are made between entry into cellular senescence as opposed to undergoing cell death in the context of DNA damaging chemotherapy. The discovery of these molecular decision points suggest new ways of eliminating senescent cells to suppress cancer-associated inflammation. For the next phase of the project, we expect to develop a potential therapeutic, based on protein-degrading technology, targeted towards key regulators of stress-induced inflammation.