Hepatocellular carcinoma (HCC) is the 3rd cause of cancer-related mortality in the world. Over 80% of HCC are associated with chronic infections by either the hepatitis B or C virus and the estimated 170 million people suffering from hepatitis C are at high risk for developing HCC. Our team studies the effects of the hepatitis C virus (HCV) proteins on hepatic physiology, notably in the context of their impact on tumorigenesis.
We are interested in HCV-mediated perturbations of inflammatory signaling, apoptosis, metabolism as well as in epithelial-to-mesenchymal transition of hepatocytes in relation to HCC initiation and progression. Finally, we collaborate with mathematicians and evolutionary biologists in a project aimed at understanding the phenomenon of cellular competition in tumour progression.
Hepatic inflammation. Persistent inflammation, characteristic of chronic hepatitis C, leads to severe liver pathology, including cirrhosis and HCC. We have shown that HCV proteins, and in particular NS5B, the viral RNA-dependent RNA polymerase, were sufficient to trigger a cascade of pro-inflammatory signaling that gives rise to the synthesis of cytokines and chemokines that in turn attract liver infiltrating hematopoietic cells. Hepatocyte-targeted invalidation of inflammatory signaling fully protects HCV-transgenic mice from virus-related tumorigenesis.
Epithelial to mesenchymal transition (EMT). Epithelial morphology and specifically the maintenance of apico-basolateral polarity is essential for the function and correct signal transduction of an epithelial cell. Its fragilisation or loss renders a cell susceptible to oncogenic transformation and gives rise to acquisition of cellular motility and invasiveness, two characteristics of metastatic cancer cells. We have shown that an HCV protein, NS5A, loosens adherent and tight junctions in hepatocytes. This viral protein cooperates with TGF-β in triggering EMT and with activated oncogenes (such as H-Ras) in increasing tumour size and invasivity in vivo.
Modulation of apoptosis. HCV developed efficient strategies of escape from the immune surveillance of the host. We have uncovered an original mechanism that participates in immune evasion: HCV NS5A protein activates cellular calpains that degrade Bid, a cellular pro-apoptotic protein of the Bcl2 family. In consequence, cells harbouring NS5A have an increased resistance to extrinsic apoptosis stimulation. We are currently engaged in a "proof of concept" approach to demonstrate the relevance of these findings in a clinical setting.
Cellular competition. In this project we use ex vivo cell culture and orthotopic injections of hepatic cells in vivo to study cellular competition of sub-populations of cancer cells. Our ambition is to better understand the molecular and cellular phenomena that govern evolution of cells during tumour progression.