Systems biology of liver cancer:
an integrative genomic-epigenomic approach (MODHEP)

Liver cancer, and mainly hepatocellular carcinoma (HCC), is one of the most common malignancies worldwide, and largely remains an incurable disease. Genetic and expression profiling studies have identified several molecular pathways that are deregulated and/or mutated in HCC. This notwithstanding, the fundamental mechanistic determinants of HCC remain largely unknown, and are confounded by highly heterogeneous molecular signatures.

The molecular bases of tumor development and progression lie in changes in sequence, structure, organization, accessibility and ultimately usage of the genome. Tumor formation and progression are accompanied by genetic and epigenetic alterations (namely post-translational modifications of DNA and associated proteins) as well as by profound changes in higher-order genomic and nuclear architecture. Some of these alterations directly cause the activation of oncogenes or inactivation of tumor suppressor genes, bringing about the abnormal properties of tumor cells. Others provide clinical parameters in cancer diagnosis and prognosis. However, how these different layers of genome organization and function evolve in emerging and established tumors, influence each other, and impact on cellular physiology and tumor progression, is essentially unknown in any type of cancer. Lack of such integrated knowledge is a major hurdle to a definitive understanding of the molecular bases of cancer development, and thus to the development of mechanism-based therapies.

The concept at the heart of MODHEP is that the pathologic behaviour of cancer cells is controlled by an abnormally reprogrammed genome: understanding cancer requires that the molecular basis for genome reprogramming be unraveled and described within an integrated model. To this aim, we are producing an integrated analysis of the nuclear changes occurring in two complementary multi-stage models of liver cancer. A coordinated, multi-faceted and quantitative series of datasets will be generated by the different labs in the consortium, forming a complete description of the genetic, epigenetic and nuclear organizational aberrations occurring both at pre-tumoral and tumoral stages of the disease. A combination of innovative systems biology-based approaches will then bring together the analysis of functional pathways with computational models of genomic, epigenomic and three-dimensional nuclear organization.

Concept of MODHEP

• generate genome-wide datasets from homogeneous cell populations in the experimental mouse models, and in part on clinical samples;
• generate a systems-based model network that integrates all the data acquired experimentally;
• assess the validity of the main features of this model network in the human disease.