“Ligue Contre Le Cancer” Labellisation
DEATH RECEPTORS and TUMOR ESCAPE
Our group tries to understand how the initial steps of the CD95 death receptor-signaling pathway occur in normal cells and how these events are overridden in malignant cells.
Death receptor CD95. CD95 (also known as Fas) is considered as a death receptor that belongs to the TNF receptor family. Its cognate ligand, CD95L is a transmembrane cytokine (m-CD95L), which can be cleaved by metalloproteases and released in the blood stream (cl-CD95L). While m-CD95L is found at the surface of immune cells where it orchestrates the elimination of transformed and infected cells, the patho-physiological role(s) of cl-CD95L remains to be elucidated. Upon CD95L binding, CD95 recruits different proteins (i.e, FADD, caspase-8/10) resulting in the formation of a complex designated DISC for Death Inducing Signaling Complex (see Figure). Ultimately, DISC formation triggers a caspase cascade that leads to the death of the cell. We found that redistribution of CD95 into plasma membrane sub-domains termed lipid rafts enhances the apoptotic signal through a yet unknown process. In addition, we recently demonstrated that in contrast to m-CD95L, cl-CD95L induces the formation of a molecular complex devoid of FADD and caspase-8/10 that we called the MISC for Motility Inducing Signaling Complex. The MISC elicits phosphoinositide-3 kinase (PI3K) activation and promotes the accumulation of activated T lymphocytes in damaged organs of systemic lupus erythomatosus patients.
Tumor escape. Most malignant cells develop subterfuges to inhibit death receptor signal transduction and to bypass the immune surveillance. For instance, the anti-apoptotic PI3K signaling pathway is found constitutively activated in numerous tumor cells. We recently observed that in leukemic cell lines, the anti-tumoral agent edelfosine abrogates the PI3K signal, which in turn elicits the clustering of CD95, its redistribution into lipid rafts and the elimination of the cells through an apoptotic signal. In addition, this CD95 compartmentalization into lipid rafts triggers the apoptotic elimination of the cells independently of CD95L. Using biophysical, molecular, biochemical and cellular approaches, our group proposes to identify the molecular mechanisms (e.g. membrane fluidity, calcium signal) underlying the redistribution of CD95 into lipid rafts and the enhancement of the apoptotic signal.
Environmental impact. Certain environmental stresses disturb the biophysical properties of the plasma membrane (i.e., membrane fluidity, composition of lipid rafts), accordingly we will further explore the impact of these environmental stresses on the initial events of the death receptor signaling.
Keywords. Apoptosis, CD95, cell signaling, cell migration, calcium signaling, membrane fluidity.