Project Details
Projekt
Functional dissection of canonical vs. non-canonical NF-κB-dependent danger signals in hepatocellular carcinoma development
Applicant
Privatdozent Dr. Mihael Vucur
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
NF-κB is a central regulator linking chronic inflammation to liver cancer and plays a major role in controlling the expression of inducible damage-associated molecular patterns (iDAMPs). NF-κB signaling is divided into a canonical and a non-canonical pathway, each expressing different target genes, which might have differential functions in distinct hepatic cell compartments during chronic liver disease and hepatocellular carcinoma (HCC). Preliminary data from a mouse model characterized by spontaneous activation of both NF κB pathways in liver parenchymal cells suggest a critical role for NF-κB-dependent DAMPs released from sublethal necroptotic hepatocytes, driving inflammation and hepatocarcinogenesis. Inhibition of necroptosis or canonical NF-κB signaling blocked DAMP release, reduced inflammation, and suppressed HCC development. Inhibition of the non-canonical pathway similarly suppressed hepatocarcinogenesis, but caused severe cholestasis and early lethality, highlighting both synergistic and distinct roles of both NF-κB pathways. Importantly, isolated NF-κB activation in either hepatocytes or cholangiocytes was insufficient to drive tumorigenesis, emphasizing the need for coordinated intercellular NF-κB signaling. P03 aims to identify the cellular sources and functional roles of NF-κB-dependent iDAMPs and to elucidate the mechanisms governing their release from hepatocytes and cholangiocytes. A particular focus will be placed on how these DAMPs mediate intercellular signaling that promotes immune activation, inflammation, and disease progression. The project will be conducted in close conceptual and methodological collaboration with other dangerhep PIs, leveraging the consortium’s shared toolbox, including two-photon microscopy (C01), transcriptomics (P09), lipidomics (P07), proteomics (P05), artificial intelligence-assisted image analysis (P01), and human biobanking resources (P08). Conceptual synergies with P05 and P06 arise particularly from the shared focus on NF-κB-driven pathomechanisms, and further disease-relevant intercellular communication (P06). Complementary expertise from P01-P04 on regulated cell death modalities - such as sublethal necroptosis (P01), apoptosis (P02), and secretory autophagy (P04) - and from P05, P08, and P09 on the role of immune cell-mediated injury further strengthen the integrative character of the project. Integration into the dangerhep consortium enables P03 to investigate how canonical and non-canonical NF-κB signaling pathways act synergistically or independently to drive cell type-specific stage transitions from chronic liver disease to tumorigenesis – with the goal of identifying NF-κB-specific signatures as potential biomarkers for high-risk patients with chronic liver disease.
DFG Programme
Research Units
