Since 1998, a new concept has emerged, based on the notion that a receptor unoccupied by its

ligand is not necessarily inactive. Rather, such a receptor can mediate two different signalling pathways, depending on whether or not it is bound by its ligand. In the absence of ligand, signalling leads to an active process that results in cell death through apoptosis. The survival of a cell expressing such a receptor can therefore be seen as dependent on the presence of the ligand, hence the concept of “dependence receptors” (DR). The fact that the different DRs trigger apoptosis in the absence of ligand suggests that they may all act as regulators of tumorigenesis. In addition, expression of DRs is lost or decreased in many tumours, suggesting that they act as tumour suppressors and that their loss represents a selective advantage for tumoral cells. The project based on the collaboration on two groups (P. Mehlen, Lyon; J. Tschopp, Lausanne) proposes that unravelling the link between specific DRs (DCC, UNC5H), downstream molecules (PIDD, caspase-2) and apoptosis will lead to the identification of new potential targets for anti-cancer drugs. The project will provide a better understanding of the signalling pathways acting downstream of DRs, observe the association of mutations with the onset and progression of tumours and generate murine models in which the apoptotic signalling of the DR is turned off to study the implication of DRs in tumorigenesis in vivo.