Research and development

Within the FATH Unit, the research groups led by Profs O. Feron and P. Sonveaux carry out research in oncology, the specific focus of which is the integration of the cancer cell in its relationship with the host. The expertise of these two groups in understanding the tumour microenvironment (hypoxia, acidosis and host cells) and the metabolic determinants of many cancers provides researchers with an original prism for dissecting the biological mechanisms leading to disease progression.

Within the host tissue, cancer cells must continually struggle to meet the bioenergetic and biosynthetic requirements necessary for their survival and proliferation. This metabolic adaptation plays an active role in metastatic dissemination and resistance to treatment. The mechanisms involved, in particular via modulation of the stroma (intercellular cooperation, angiogenesis, immune anergy, etc.), are examined using cell and animal models adapted to the types of cancer studied.

Several translational projects arising from this research are aimed at the preclinical and clinical development of new anti-cancer drugs targeting different aspects of tumour cell biology, including mitochondrial oxidative stress, reticulum stress and autophagy.

The FATH unit has recognised expertise in the analysis of signalling and pharmacology, in particular that of nitric oxide synthases (NOS) in the heart and blood vessels. In particular, FATH has developed techniques for analysing the molecular regulation of membrane receptors and intracellular effectors (including NOS) in animal and human myocardium and vessels (e.g. via PI3K- and Akt-dependent phosphorylation, interaction with chaperones such as hsp90, and other regulators such as caveolins). FATH uses different strains of transgenic mice and cardiovascular tissues of human origin obtained in collaboration with Clinical Services at the IREC. Within the Pole, the laboratory is equipped with state-of-the-art instruments for biochemical, molecular and cellular analyses (including IONOPTIX platforms equipped to measure sarcomeric shortening and calcium fluorescence in myocytes) and animal phenotyping (e.g. by miniaturised implantable telemetry for mice).

Biology of NO synthases. Following on from the work of Prof. J-L. Balligand and Prof. C. Dessy on the role of NO in cardiac contractility and vascular relaxation respectively, these projects are studying the transcriptional and post-translational regulation of NO synthetase isoforms, eNOS, nNOS and iNOS in in vitro cell cultures and animal models (in vivo) of cardiovascular pathologies.

Study of the endothelial phenotype characteristic of ischaemia/reperfusion conditions. This work aims to identify the molecular determinants of post-ischaemic angiogenesis (Prof. O. Feron) and to better characterise the phenomenon of ischaemic preconditioning at the origin of the survival advantages for cells of the cardiovascular system exposed to haemodynamic stress (Prof. C. Dessy).

Mechanistic study of the determinants of adaptive or maladaptive remodelling of the stressed myocardium. Initially carried out in collaboration with a European network ("EUGeneHeart" Consortium, subsidised by the European Commission) and a transatlantic network of excellence (subsidised by the Fondation Leducq), this project includes the study of paracrine factors influencing the tissue regeneration potential of cardiac progenitor cells and signalling between cardiac myocytes and fibroblasts and endothelial cells. The reciprocal influence of metabolism on remodelling (including stem cell biology) is studied in the context of different myocardial stresses (haemodynamic overload, neuro-humoral stimulation).

For all these projects, the new mechanistic targets are validated in humans using human tissues and bioinformatics analysis of polymorphisms in databases from GWAS studies.

A good example is the characterisation of the role of the Beta3 adrenergic receptor in the human myocardium, which justified the launch of a randomised, controlled and prospective clinical trial testing the protective effect of a Beta3 adrenergic agonist in patients at risk of developing heart failure with preserved ejection fraction.