Targeting the Wnt/beta-catenin cell signalling pathway in liver primary cancers – BetaCatHCC

Hepatocellular carcinoma (HCC) is one of the most common cancers in men and the third most common cause of cancer mortality, worldwide. Most chronic liver diseases from either viral (Hepatitis B and C viruses), nutritional, toxic or drug-related, metabolic or genetic origins may lead to fibrosis and cirrhosis, from which 80% HCC arise. When possible, curative surgical treatments of HCC include tumour resection and liver transplantation. Non-surgical treatments include alcoholisation, chemoembolization, selective radiation therapy and biotherapies targeted to angiogenesis and/or cell signalling pathways. Despite main advances, the efficacy of these innovative treatments appears however limited and the prognosis of HCC remains poor, yet. Today, the main challenges facing HCC treatments include: the detection of the early stages of HCC and the evaluation of the aggressiveness, vascularisation and metabolic activity of the tumour; the identification of predictive factors of the efficacy of conventional treatments; the development of new therapeutic strategies, including combination of conventional and bio-therapies. Thus, a detailed understanding of how genomic and molecular alterations select for distinct molecular pathways during the development of HCC is necessary to improve the screening, prevention, and treatment of HCC in patients with chronic liver diseases.
The project is focused on the Wnt/?-catenin cell signalling pathway, a central regulatory system in both normal and transformed liver cells whose deregulation is involved in ~30% of HCC. The objectives of the project include (i) to decipher the molecular mechanisms responsible for a constitutive activation of the Wnt pathway in HCC, as a result of non-mutational events; (ii) to identify sets of biomarkers of liver cancer progression, with specific Wnt signature based on the analysis of two cohorts, each representative of the major etiologic factors, namely HBV-positive and HCV-positive hepatocellular carcinoma in South-Korea and France, respectively; (iii) to model a deregulation of the Wnt/?-catenin signalling pathway in animal model systems for testing innovative therapeutic strategies and biomarkers.
The proposal will be conducted by four complementary teams involved in basic and translational research on hepatocarcinogenesis, Wnt/?-catenin cell signalling pathway, and pericellular matrix, in Rennes, Paris, Daejon and Seoul. The outcome of the project should help in characterizing new drug targets and biomarkers targeted to the tumor microenvironment, relevant to personalized therapies of liver cancers.