"While it is assumed that transmembrane receptors are active only in the presence of ligand, we have proposed that some receptors may also be active in the absence of ligand stimulation. These receptors, named “dependence receptors” (DRs) share the ability to transmit two opposite signals: in the presence of ligand, these receptors transduce various classical “positive” signals, whereas in the absence of ligand, they trigger apoptosis. The expression of dependence receptors thus creates cellular states of dependence for survival on their respective ligands. To date, more than fifteen such receptors have been identified, including the netrin-1 receptors DCC (Deleted in Colorectal Cancer) and UNC5H1-4, some integrins, RET, EPHA4, TrkA, TrkC and the Sonic Hedgehog receptor Patched (Ptc). Even though the interest in this notion is increasing, two main questions remain poorly understood: (i) how very different receptors, with only modest homology, are able to trigger apoptosis when unengaged by their respective ligand, and (ii) what are the respective biological roles of this pro-apoptotic activity in vivo. We have hypothesized that the DRs pro-apoptotic activity is a mechanism that determines and regulates the territories of migration/localization of cells during embryonic development. We also demonstrated that this may be a mechanism that limits tumor growth and metastasis. The goal of the present project is, based on the study of a relatively small number of these receptors –i.e., DCC, UNC5H, RET, TrkC, Ptc- with a specifically larger emphasis on netrin-1 receptors, to address (i) the common and divergent cell signaling mechanisms triggering apoptosis downstream of these receptors and (ii) the physiological and pathological roles of these DRs on development of neoplasia in vivo. This latter goal will allow us to investigate how this pro-apoptotic activity can be of use to improve and diversify alternative anti-cancer therapeutic approaches."