Our group works along two lines aiming at both better understanding and improvement of treatments of two life-threatening diseases, cancer and severe chronic viral infections.
Transcriptional Mechanisms of Oncogenesis and Resistance to Chemotherapies
Transcription factors constitute essential molecular platforms for the integration of intra- and extracellular signals, the activity of which is regulated by a number of post-translational modifications. Yet, the molecular mechanisms whereby their deregulation alter gene expression within chromatin to permit adaptation of cancer cells to their environment are still ill-defined. In this context, we are addressing two complementary issues. Firstly, we are investigating why and how two proteins related to the c-Fos proto-oncoprotein, Fra-1 and Fra-2, contribute to the metastatic phenotype in the breast tumors where they are overexpressed in hyperphosphorylated due to perverted cell signalling. This question is particularly important as metastatic breast cancer is the main cause of death by cancer amongst women. Secondly, we are studying how redox metabolism and transcription factor sumoylation (a post-transcriptional modification related to ubiquitin often altered in tumors) control the expression of transcriptomes and are involved in tumorigenesis and resistance to chemotherapies. To this aim, we are combining large-scale genomic and transcriptomic approaches to functional studies, both in vitro and in vivo in mouse models as well as using patient samples, with a special emphasis on leukemia with bad prognosis.
Keywords : breast cancer, leukemia, chemotherapy, Fos, Jun, AP-1, SUMO, ubiquitin/proteasome, cell signalling, transcriptome, large-scale genomic studies, redox metabolism
Immunotherapy of Cancer and Severe Viral Infections
Monoclonal antibodies are the main class of biotherapeutics with applications in many diseases, including cancer and severe infections. Yet, their use in the clinic is currently far from optimal for long-term treatment of chronic diseases. In particular and curiously, mAbs have little been considered in the antiviral arsenal till recently and only their neutralizing activity is considered despite the fact that they interact functionnally with other components of the immune system. We are therefore addressing whether antiviral mAbs might also constitute immunomodulatory agents influencing the endogenous antiviral immunity of infected hosts and, thereby, the long-term efficacy of treatments. In vivo studies with human viruses being currently impossible due to many technical and ethical limitations, this work is conducted in the context of a leukemia induced in immunocompetent mice upon infection a the lethal retrovirus (FrCasE) and treated with neutralizing mouse mAbs that have been molecularly characterized in the laboratory. The use of such a model allows, not only statistical analysis, but also access to numerous immunological tools and genetically-engineered animals not available in other species. Using it, we have recently discovered that short mAb treatments can induce a long-lasting TH1protective endogenous antiviral immune response responsible for healthy survival of infected mice under appropriate conditons of immunotherapy. The therapeutical consequence of this observation is potentially high and will have to be considered for future passive immunotherapies of life-threatening infections by persistent viruses such as HIV or HCV, as the current chemotherapies or interferon-based treatments are not endowed with such a property. The paramount question we are now facing is to elucidate the cellular and molecular mechanisms responsible for the induction of such a protective antiviral immunity, with a particular emphasis on the interaction between immune complexes formed during the immunotherapy and the various immune cell types. This is addressed in vaccination experiments conducted in different engineered mouse genetic backgrounds as well as in various ex vivo assays involving immune cells of various types (pDC, cDCs, T and B cells, NKs).
Keywords: cancer, virus, immunotherapy, monoclonal antibody, vaccine-like effects, dendritic cells, T and B lymphocytes, T regs, immunogenic death