Seminars

1)Although extracellular vesicles (EVs) are now well-recognized organelles, their diversity in terms of mechanisms of secretion and functional role is poorly evaluated.  We have shown in vivo that CD133, in conjunction with actin cytoskeleton and membrane phospholipids, promotes the biogenesis and secretion of Extracellular Vesicles (EVs) from epithelial microvilli with functional activity in development. We hypothesized that these CD133-EVs likely represent a new subtype of EVs emanating from epithelial cell protrusions, which in addition to their role in development, may also be involved in promoting epithelial cancer aggressiveness. Indeed, in several tumor types including breast cancer, CD133 is a bad prognosis marker, its levels being correlated with adverse outcomes and chemotherapy resistance. We therefore postulate that high levels of CD133 in breast cancer cells may be critical for triggering overproduction of CD133-EVs contributing to cancer invasion and metastasis. We have undertaken i) a detailed characterization of CD133-EVs secreted by breast cancer cells, ii) uncover their function in tumor angiogenesis in vitro, iii) the study of their involvement in premetastatic niche formation in vivo, and iv) a careful analysis of the clinical relevance of CD133-EVs using liquid biopsies. In my talk I will summarize some of the latest data on these topics.

2)Caveolae are small invaginated nanodomains of the plasma membrane that have been classically involved in membrane trafficking and signaling. In 2011, we have established these multifunctional organelles as key mechano-sensors that adapt the cell response to variations in membrane tension induced by various types of mechanical stress1. We have now investigated the role of caveolae mechanics in the control of intracellular signaling pathways. Using state-of-the-art super resolution imaging in live cells combined with machine-learning network analysis, we show that in response to mechanical stress, caveolae disassemble into smaller scaffolds made of non-caveolar caveolin 1 (Cav1) - which display increased mobility at the plasma membrane. Mechanical stress promoted the direct interaction of Cav-1 scaffolds with several signaling molecules, resulting in the regulation of their signaling output. Our results therefore establish a new paradigm in mechanotransduction whereby caveolae act as mechano-signaling hubs that couple the sensing of membrane tension variations to the remote control of intracellular signaling through the release of Cav1 scaffolds actively diffusing at the plasma membrane.