Pascal Therond

Responsabilités


Distinctions

  • 2015 : Cancer Prize "Gallet et Breton" by the National academy of medicine
  • 2009 : Prize "Victor Noury" by the Academy of sciences
  • 2001 : EMBO Young investigator programme

Biographie

Pascal Therond and his research team has identified a new mechanism by which cells exchange information during embryogenesis : the ESCRT proteins involved in the budding of viral particles are also necessary for secretion of Hedgehog molecules required for embryonic development.

In collaboration with the teams of Maximilian Fürthauer and Sandrine Pizette (iBV, Nice Sophia Antipolis University), he has just identified this mechanism by combining experimental approaches using genetics, biochemistry and ultrastructural analysis (Matusek et al., Nature 2014). His team showed that the secretion of Hedgehog depends on a protein complex, evolutionarily conserved from yeast to humans, called ESCRT (Endosomal Sorting Complex Required for Transport). Elimination of ESCRT activity in the animal blocks the secretion of Hedgehog and decreases its long range activity. Moreover, his team showed that the Hedgehog and ESCRT proteins are secreted together on vesicles which spread in the extracellular space and are detected on the surface of target cells. Numerous studies have established that the ESCRT proteins are essential for the budding of viral particles from the surface of infected cell. This study shows for the first time that in a healthy organism, the ESCRT proteins control the budding of extracellular vesicles containing a signaling molecule of major importance for embryonic development.

The implications of this study are multiple. Hedgehog is one of the "signaling" molecule necessary for embryonic development and highly conserved in the animal kingdom. Moreover its function is at the connection between the embryonic developmental program and tumorigenesis in humans since its deregulation is involved in the development of several cancers including those of the gastro-intestinal tract, prostate, brain and lungs. The link that Hedgehog provides between these two mechanisms is a case study (Briscoe and Thérond, Nature Review Molecular Cell Biology, 2013) which, since its initial identification in the fruit fly Drosophila melanogaster, has recently led to the development of anti-cancer drugs in humans. These clinical advances illustrate the close link between basic research and medical research. Understanding how the secreted molecule Hedgehog exerts its effect on surrounding cells is necessary for understanding tumor development. For example, in some solid tumors, Hedgehog contributes to the proliferation and maintenance of the cancer "stem" cells. Many studies show that Hedgehog induces changes of the tumor "micro-environment" acting in a paracrine manner. But the vehicle that secreted Hedgehog uses was unknown until now. These new results suggest that Hedgehog contributes to the proliferation of cancer cells by being transported on special vehicles, secretory vesicles that pass through the extracellular space. It is becoming increasingly clear that these vesicles have specialized functions, including tumor progression and metastasis. Analysing the behavior of these vesicles is essential in order to better understand tumorigenesis.