Programmed cell death is a fundamental biological process that ensures tissue development and repair following damage or pathogen infection. However, when deregulated, cell death can have severe pathological consequences. It has been known for long time that evasion of cell death is a hallmark of cancer. On the other hand, it recently became clear that aberrant cell death is a causative factor for inflammation and inflammation-related disorders. In addition to its role in auto-inflammatory and auto-immune diseases, inflammation fuels malignant cell growth and favour the evasion of anti-tumour immunity. Therefore, the relationship between cell death and cancer might go beyond the evasion of cell death programs by cancer cells. It is conceivable to believe that cancer cells have the ability to manipulate cell death programs to promote an inflammatory microenvironment that promotes their own growth.
In our laboratory we want to address the following scientific questions:
One of the best models to study the mechanisms governing the life and death decision in the TNF/TNFR1 system. TNFR1 is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and the binding to its cognate ligand, TNF, elicits a cascade of events leading to the activation of pro-inflammatory and pro-survival genes. However, under certain circumstances, TNF can induce cell death (Figure 1). In the last few years important insights have been gained on what determines whether the outcome of TNFR1 stimulation is gene expression or death. However, many aspects of this decision-making process are still far from being fully understood.
Using a series of genetic and biochemical approaches we want to further investigate the molecular mechanisms that control the outcome of TNFR1-mediated signaling pathway. Given the importance of the TNF/TNFR1 system in innate immune responses against pathogen infection and tissue damage, a better characterization of the mechanisms controlling this pathway will help the understanding of innate immunity regulation.
Figure 1.TNF signaling pathway. Binding of TNF to TNF-R1 leads to receptor trimerization and formation of TNF-R1 complexes, referred to as complex-I, whose ultimate function is to trigger inflammatory and pro-survival gene induction. RIPK1 in complex-I can dissociate form the plasma membrane bound TNF-R1 complex and nucleate a secondary cytoplasmic complex, complex-II, that has the potential to trigger apoptosis or necroptosis. A number of different checkpoints exist that control the formation and cytotoxic potential of complex-II: (1) Ubiquitin-dependent checkpoint,; (2) Phosphorylation-dependent checkpoint; (3) Transcription-dependent checkpoint, based on NF-kB-mediated upregulation of pro-survival genes; and (4) caspase-mediated cleavage and inactivation of RIPK1, RIPK3 and CYLD, mediated by a cFLIP/caspase-8 heterodimer, which ultimately prevents apoptosis as well as necroptosis.
TNF signaling pathway is tightly regulated by different checkpoints (Figure1), the deregulation of which can skew the response towards cell death, in the forms of apoptosis and necroptosis. Exacerbated cell death can then lead to chronic inflammation (Figure2). It is indeed now clear that several auto-inflammatory and auto-immune disease, such as psoriasis and Chron’s disease, are caused by aberrant TNF-induced cell death that is mediated by the kinase activity of RIPK1 (Figure1). RIPK1 kinase inhibitor was recently tested in clinical trials for cell death-dependent inflammatory diseases and then “moved back to research”, indicating that more will have to be understood on the relationship between cell death and inflammation.
Using a series in vitro and in vivo approaches we want to further investigate how the deregulation of RIPK1-mediated cell death causes chronic inflammation. This might help find new strategies for the treatment of chronic inflammatory diseases with a cell death dependent etiology.
Figure 2. Aberrant cell death in chronic inflammation.( A) Cell death is important for the repair and regeneration programs different types of tissues, such as the epithelium of skin and intestine. Dying cells release soluble factors that trigger the activation of an inflammatory program whose ultimate purpose is to restore tissue integrity. (B) However, deregulated cell death determines the persistence of tissue repair programs that in turn leads to chronic inflammation and epithelial cell hyperproliferation, and, ultimately, to auto-inflammatory and auto-immune diseases.
Malignant cells have the ability to hijack host inflammatory programs to promote their own growth and migration and to dampen anti-tumour immunity. Since deregulated cell death can promote inflammation, we want to understand whether and how cancer cells manipulate different cell death programs to modulate inflammatory responses in a way that inhibits anti-tumour immune responses (Figure 3). To do so we will use autochthonous mouse tumour models as well as tumour cell lines where essential components of different cell death pathways were genetically deleted. This might lead to a better understanding of how malignant cells elude the immune system with the ultimate purpose to improve current immunotherapy.
Figure 3. Potential mechanisms of cell death-induced tumour immune evasion. Malignant cells have the ability to adapt to the host immune system pressure and ultimately evade recognition and elimination by the T cells. They can do this by hijacking inflammatory programs from the host organism in order to create an immune-suppressive microenvironment that dampens anti-tumour immunity. Cell death program manipulation could be one of the mechanisms allowing cancer cells to create such an inflammatory microenvironment.
