CANCERSYS

"Mathematical modelling of beta-catenin and ras signalling in liver and its impact on proliferation, tissue organization and formation of hepatocellular carcinomas"

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 Obiettivo del progetto (Objective)

'The goal of the CANCERSYS project is to establish a multi-scale model for two major signalling pathways involved in the formation of hepatocellular carcinoma, the beta-catenin and ras signalling pathways. Integrative studies linking measurements in primary heptocytes with effects at the organ level will address the impact of these signalling networks on proliferation, tissue organization and formation of hepatocellular carcinoma. In a close collaboration of scientists from theoretical fields and life sciences, our approach will combine dynamic modelling of signalling networks with spatial-temporal modelling of the liver microarchitecture. For this purpose dynamic models of the beta-catenin and ras core modules and their interactions will be integrated into a single-cell based three-dimensional model of the liver lobule. This model will be used to predict the impact of beta-catenin and ras activation on tissue organization starting with the early events, such as enhanced proliferation as well as micromotility of single cells, followed by formation of nodules and finally of dedifferentiated hepatocarcinomas. Predictions obtained by the model will be validated by inducible Apclox/lox and Ha-rasQ61R mouse strains, which have already been established by members of our consortium and allow induction of hepatocellular carcinoma. In addition the model predictions of the combined influence of active beta-catenin and ras signalling will be validated using a mouse strain that allows induction of both pathways in hepatocytes. In an iterative process, the model will be validated and adjusted to the in vivo situation. The model aims at the identification of systems properties of beta-catenin and ras signalling exploited during carcinogenesis and will foster the prediction of strategies for effective intervention, thereby facilitating the design of novel therapeutic strategies to combat hepatocellular carcinoma.'

Introduzione (Teaser)

Carcinogenesis is a complex process involving activation or silencing of various signalling pathways. A European consortium decided to model the combined influence of two cancer-related pathways in the development of liver cancer.

Descrizione progetto (Article)

The liver is a vital organ of multiple functions, including protein synthesis, detoxification and production of digestive enzymes. Understanding how cells establish the structure of the liver and how they behave during regeneration or cancer formation is poorly understood.

To contribute to knowledge in this area, the EU-funded Cancersys project focused on developing a model of liver architecture and hepatocellular carcinoma. Firstly, project members established a procedure for tissue spatial-temporal modelling based on confocal laser scans, image processing and three-dimensional tissue reconstruction. This technique was applied to understand liver microarchitecture during cancer formation.

The Cancersys model captured liver lobule structure, focusing on veins, and normal and malignant cell types. It facilitated the analysis of various parameters such as cell proliferation status and rate, cell death rate and three-dimensional cell orientation during tumour formation.

In a second step, the beta catenin and ras signalling pathways were integrated in the model. The aim was to predict the impact of the activation of these cancer-related pathways on single cell decision and tissue organisation.

By coupling the modelling approach with whole genome expression profiling from hepatocytes with activated beta-catenin or ras signalling, scientists identified negative interactions between both pathways. Signalling through beta-catenin led to attenuation of expression of genes that are positively regulated by the ras signalling module and vice versa. Project scientists planned to test candidate molecules responsible for this interaction in transgenic mice of inducible beta-catenin and ras signalling.

The Cancersys model offered a predictive approach for determining the role of cancer-related signalling cascades in hepatocellular carcinoma. Partners are hopeful that their model will lead to the design of effective intervention and therapeutic strategies against cancer.