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Scientific orientation of Liccardi Lab (Genetic instability, cell death and inflammation Lab)

The overarching theme of my research consists in understanding the physiological crosstalk between cell death and survival, and how this impacts on immunity. This functional interplay controls not only physiological responses but, when perturbed, can be causative of many pathologies such as cancer, autoimmune diseases, response to viral infections. The understanding of how cells undergo or avoid different modalities of cell death is central to uncover the disruption or maintenance of tissue homeostasis and how these contribute to pathological conditions. Importantly the molecular understanding of this evasion is fundamental to understand how to intervene therapeutically to either re-activate cell death (in case of cancer) or inhibit inflammation (in the case of inflammatory and autoimmune disorders). Within these overarching concepts my lab focuses on two fundamental and intercalating biological aspects: 1) Genomic Instability-induced Cell Death and Inflammation (G.I.C.D.I) and 2) Death Ligands and TNF signaling induced Cell Death and Inflammation (D.L.T.C.D.I).

G.I.C.D.I.: The acquisitions of gross cellular mutations like micronuclei and cytoplasmic DNA contributes to tumorigenesis but also a chronic or acute inflammatory response mostly driven by interferon type I that alone can lead to the pathogenesis of many inflammatory and autoimmune conditions. In my lab, we have discovered that while type I interferon response induces specific immunological and inflammatory outcomes, it also upregulates many genes involved in different modality of cell death such as Necroptosis providing therefore a priming to undergoing specific modalities of cell death. Our aim is to harness genomic instability by studying the resulting inflammatory activation, and utilize this as a vulnerability by designing therapeutic approaches aimed at engaging fully the cell death potential provided by this priming.

Importantly, many patients currently suffering from different types of Interferonopathies often develop lesions in different tissues suggesting that also in these case, activation of the interferon response pathway drives activation of cell death. We study how cell death induced inflammation contributes to the pathology of these conditions by utilization of clinical samples and datasets as well as animal models that have been designed to recapitulated these diseases.

D.L.T.C.D.I: Central to our research is understanding the activation and inactivation of cell death modalities and hence the binomial relationship between cell death and survival. The study of the Death ligands (DL) and TNF signaling in mediating cell death responses becomes, therefore, incredibly complementary and central to uncover how genomic instability impacts cell death and inflammation.  By looking at the regulation of TNF signaling system as well as DL induced activation of the Death receptors Trail-R and CD95, we investigate how the perturbation of this cellular signaling output impacts on development as well as the propagation of different cancer entities (especially Small Cell Lung Cancer: SCLC and Non-SCLC, Chronic lymphoblastic Leukemia: CLL and Diffuse Large B-Cell Lymphoma: DLBCL).  Furthermore, the activation of gene activatory signals (NF-kB) downstream of TNFR1, the Death Receptors as well as many immune receptor signaling complexes is regulated by the Linear ubiquitin binding assembly complex (LUBAC). This complex is the only known complex capable of catalysing the formation of linear ubiquitin chains. LUBAC is known to have a fundamental role in maintaining tissue homeostasis during development as well as in regulating NF-kB driven activation and therefore in counteracting cell death activation. In the lab we are also very interested in understanding the role of LUBAC in cancer biology and how regulation of linear ubiquitin chains drives inflammatory diseases.