Dataset Information

IL-6 Signalling

ABSTRACT: The pro-inflammatory cytokines interleukin 1 (IL-1) and 6 (IL-6) are crucially involved in the regulation of a multitude of physiological processes, in particular coordinating the immune response upon bacterial infection and tissue injury. Both interleukins induce complex signalling cascades and trigger the production of mitogenic, pro-proliferative, anti-apoptotic, chemotactic, and pro-angiogenic factors thereby affecting the delicate balance between regenerationvs. invasive growth, tumourigenesis and metastasis. Moreover, several links to insulin resistance have been found within their associated signalling networks. Focusing on this from a systems biology perspective, we introduce comprehensive large-scale network models of IL-1 and IL-6 signalling which are based on a logical modelling approach and reflect the current biological knowledge. Theoretical network analysis enabled us to uncover general topological features and to make testable predictions on the stimulus-response behaviour of the networks. In this context, non-intuitive network-wide species dependencies as well as structures of regulatory feedback and feed-forward mechanisms could be characterised. By integrating high-throughput phosphoproteomic data from primary human hepatocytes we optimised the model structures to obtain models with high prediction accuracy for hepatocytes. Our model-based data analysis, for instance, suggested model modifications regarding (i) Akt contribution to IL-1-stimulated p38 MAPK activation and (ii) insignificant p38 MAPK activation in response to IL-6. In light of the presented results and in conjunction with the detailed model documentations, both models hold great potential for theoretical studies and practical applications.

SUBMITTER: Tomas Helikar

PROVIDER: 2314 | Cell Collective |

REPOSITORIES: Cell Collective

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Publications

Large-scale network models of IL-1 and IL-6 signalling and their hepatocellular specification.

Ryll Anke A Samaga Regina R Schaper Fred F Alexopoulos Leonidas G LG Klamt Steffen S

Molecular bioSystems 20111003 12

The pro-inflammatory cytokines interleukin 1 (IL-1) and 6 (IL-6) are crucially involved in the regulation of a multitude of physiological processes, in particular coordinating the immune response upon bacterial infection and tissue injury. Both interleukins induce complex signalling cascades and trigger the production of mitogenic, pro-proliferative, anti-apoptotic, chemotactic, and pro-angiogenic factors thereby affecting the delicate balance between regeneration vs. invasive growth, tumourigen ...[more]

PMID: 21968890

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Project description:The colorectal epithelium is a rapidly renewing tissue, with a remarkable capacity to regenerate following injury. In colorectal cancer (CRC), this regenerative capacity can be co-opted to drive epithelial plasticity. Activation of oncogenic MAPK signalling in CRC is common, with mutations frequently found in both KRAS (40-50%) and BRAF (10%), alongside other mechanisms of EGFR pathway upregulation. Nonetheless, inhibition of this pathway is often linked to rapid therapeutic resistance in patients. Given the recent development of KRAS inhibitors and the licensing of BRAF+EGFR inhibitor combinations we have investigated mechanisms of resistance to these agents in complex mouse models of CRC. Here we show that MAPK signalling supports the regenerative/revival stem cell phenotype in vivo, while its inhibition leads to rapid remodelling of both Kras and Braf mutant mouse models to a high Wnt activity canonical stem cell phenotype marked by expression of Lgr5. This results in acute therapeutic resistance in Kras driven, and delayed resistance in Braf driven models. Importantly, where therapeutic MAPK targeting is applied in the presence of a single regenerative epithelial population, such as early metastatic disease, or where plasticity is restrained, for example through Wnt pathway restriction, a marked impact on tumourigenesis is observed. Modelling of an BRAF and RNF43-mutant patient population, clinically super-responders to BRAF/EGFR inhibitor therapy, demonstrates excellent response to therapy due to restricted epithelial plasticity, highlighting the criticality of cellular plasticity in therapeutic response. Together, our data provide clear insight into the mechanisms underpinning resistance to targeting oncogenic MAPK signalling in CRC. Moreover, we demonstrate that strategies that aim to restrict epithelial plasticity or corral into or intervene when tumours are in a regenerative cell fate may improve efficacy of MAPK targeting agents in CRC.

Dataset Information

IL-6 Signalling

Publications

Large-scale network models of IL-1 and IL-6 signalling and their hepatocellular specification.

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