Abstract 5235: A model for TNFα-mediated NFκB signalling: A systems biology study on hepatocytes and liver cancer cells.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC It is known that the development of hepatocellular carcinoma (HCC) is frequently associated to inflammation, hepatocytic inhibition of apoptosis, and compensatory liver regeneration. In this context, the classical κ-light-chain-enhancer of activated B cells (NFκB) signaling pathway is one central regulator of inflammatory responses and hepatocyte survival, which may promote HCC development. Upon stimulation, Kupffer cell-derived cytokine tumor necrosis factor (TNF)-α is one of the key factors during the priming phase of liver regeneration as well as in hepatocarcinogenesis mainly driving cell survival and proliferation by NFκB signalling pathway. In order to understand the impact of this pathway in the earliest stages of liver damage and tumorigenesis, mathematical modelling is necessary to describe the dynamic behaviour of this pathway in normal as well as in malignant-transformed cells. Several mathematical models have been developed for TNFα-induced NFκB signalling in immortalized fibroblasts and tumor cell lines; however, a model specifically analyzing and comparing hepatocytes and HCC cells is still missing. We here present a hepatocyte-specific ordinary differential equation (ODE) model for TNFα-induced NFκB signaling that considers experimental data of protein expression after TNFα stimulation (p65/pp65, IκBα/pIκBα), basal protein turnover (p65, IκBα), and IκBα mRNA. In order to sufficiently describe the pathway dynamics, an additional nuclear phosphorylation step of p65 was included in the model. Possible candidate kinases are the mitogen- and stress-activated protein kinase1 (MSK1) and the protein kinase C zeta (PKCζ). The established model was able to predict TNFα-induced p65/IκBα complex formation, which was experimentally confirmed using primary mouse hepatocytes cells. Finally, we compared the dynamics of TNFα-induced NF-kB pathway activation in different species and cell types (primary murine hepatocytes, human and mouse HCC lines, mouse liver tissue after partial hepatectomy). In conclusion, we here present a mathematical model for TNFα/NFκB signalling in primary hepatocytes cells, providing an important basis to quantitatively disentangle the complex processes factors in liver regeneration and tumorigenesis. Citation Format: Federico Pinna, Sven Sahle, Katharina Beuke, Michaela Bissinger, Selcan Tuncay, Lorenza D'Alessandro, Ralph Gauges, Andreas Raue, Jens Timmer, Ursula Klingmuller, Peter Schirmacher, Ursula Kummer, Kai Breuhahn. A model for TNFα-mediated NFκB signalling: A systems biology study on hepatocytes and liver cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5235. doi:10.1158/1538-7445.AM2013-5235