STRESS, MEMBRANE AND SIGNALING

Plasma membranes are the first targets of exogenous stress. We have previously shown that early membrane remodeling (changes in fluidity and reorganization of lipid rafts) plays an important role in cell responses towards various stresses. Our project is aimed at identifying the early molecular mechanisms involved in the toxicity of pollutants or the cytokine TRAIL (TNF-Related Apoptosis Inducing Ligand), possibly in association with lifestyle or diet factors (ethanol, omega-3), short chain fatty acids (SCFA; propionibacteria or acidic stress). The outcome of this work should help proposing new toxicity biomarkers and strategies to prevent cytotoxic effects of chemical compounds; it might also help rendering TRAIL more efficient to improve anticancer therapy. The contribution of membrane remodeling to cystic fibrosis (CF), an inflammatory disease from a pulmonary and systemic point of view, are also being studied.

1-Membrane signaling and phenotypic responses induced by environmental pollutants in healthy or diseased cells (steatotic cells). Membrane remodeling and signaling are studied following treatment with PAHs or phthalates in combination or not with ethanol or dietary lipids. Both in vitro (rodent or human cell lines: hepatocytes, endothelial cells, blood cells) and in vivo models (Zebrafish larvae) are used. A special focus is brought to the impact of pollutant exposure on the disease progression of liver steatosis (ANR CESA project “STEATOX”). Various factors involved in membrane remodeling (reactive metabolites, alteration of lipid metabolism enzymes, oxidative stress, ionic homeostasis [H+ and Ca2+]) are investigated. In addition, we explore the connection between the modulation of the plasma membrane physicochemical parameters and the intra- and extracellular signaling triggering cell fate. Our project is performed notably thanks to our Membrane Stress Plateau.

2-Modulation of TRAIL signaling by SCFA/propionibacteria or acidic extracellular pH (pHe). We study the molecular mechanisms responsible for synergy of TRAIL with SCFA. The synergy between propionibacteria and TRAIL is investigated in in vivo colon cancer models. A propionibacterial expression and secretion plasmid developed in STLO (INRA, Agrocampus Ouest, Rennes) is being adapted for a strong and constitutive secretion of TRAIL (brevet FR10/53750, WO11141558); the recombinant strain will be tested in vivo. An acidic pHe is a characteristic of human solid tumors and switches TRAIL-induced apoptosis to necroptosis. In this context, we search for new RIPK1 partners and new potential RIPK1 and RIPK3 inhibitors.

3-Role of lipids in inflammation associated with cystic fibrosis. The loss of CFTR function causes lipid homeostasis impairments which might contribute to chronic inflammation in cystic fibrosis (CF). Macrophages are involved early in the inflammatory process. However they are poorly studied in CF. Moreover, it was demonstrated that determining how CFTR is involved in the metabolism of some lipids would be important for understanding the CF pathophysiology. In this context, we seek to understand how defective CFTR affects cellular lipid homeostasis and if there is a link with inflammation  and function of primary human macrophage. This should help elucidating the importance of CFTR’s role in CF pathophysiology (supported by “Vaincre La Mucoviscidose”).

4-Identification of the Ca2+ channels and Ca2+-dependent mechanisms driving cancer cell migration and invasion. Our study deals with the role of TRPVs in the metastatic transformation of melanoma cells (supported by the Ligue Grand Ouest contre le cancer and ARC foundation). In this context, we also look for new potential TRPV inhibitors.