Apoptosis, cancer and development
The team originally proposed the dependence receptor theory. These receptors have a dual signaling ability : when bound to their ligand they induce survival pathways, whereas they induce an active signal of cell death in the absence of their ligand. The team currently works on three approaches: (1) deciphering the molecular mechanisms of dependence receptor-induced cell death; (2) characterizing new dependence receptors; (3) analizing the physiological role of these receptors in tumor progression. Finally, the team aims at transforming basic knowlegde into therapeutic approaches to restore cell death induced by these receptors in tumors.
Our team investigates all aspects related to dependence receptors (DR). These receptors have a dual signaling ability: in the presence of their cognate ligand they induce a survival signal, whereas they transduce an active apoptotic signal in the absence of such ligands. More than twenty such receptors have been described to date and we speculated that their activity is instrumental for embryonic development as well as for the regulation of tumorigenesis (Mehlen et al., 2011, Nat Rev Cancer).
This concept of dependence receptors arose by highlighting the importance of such receptors in developmental processes and in tumor development. We initially proposed that the dependence receptor function was important to regulate migration and localization of cells during development (for example neurons and endothelial cells) (Thibert et al., 2003, Science; Mille et al., 2009, Nature Cell Biology; Castets et al., 2009, Dev Cell). We also showed that they had a tumor suppressive function by limiting tumor cell development in the absence of their ligands (Mazelin et al., 2004, Nature; Castets et al., 2012, Nature). Beyond the fact that the loss of receptors can lead to tumor progression, we have also shown that tumoral escape can be achieved through autocrine secretion of the ligand by cancer cells (Fitamant et al., 2008, PNAS). This observation led us to propose a therapeutic strategy based on inhibiting the binding of ligands, thus restoring the pro-apoptotic function of dependence receptors (Delloye-Bourgeois et al., 2009a, JEM; Delloye-Bourgeois et al., 2009b, JNCI; Bouzas-Rodriguez et al., 2010, JCI).
An antibody blocking the interaction between Netrin-1 and its dependence receptors was preclinically developed (Grandin et al., Cancer Cell 2016) and has been tested in patients with advanced cancer since 2017 as part of a phase 1 trial with very encouraging clinical results
Today, the overall project of the team members has two facets:
1) the deepening of knowledge on molecular mechanisms downstream of these receptors, and thus, better understand of their implications on tumor progression.
2) aims to support the translation of the research observation to clinical trials.